Content uploaded by Urs Boutellier
Author content
All content in this area was uploaded by Urs Boutellier
Content may be subject to copyright.
Eur J Appl Physiol (2006) 97: 643–663
DOI 10.1007/s00421-006-0238-1
REVIEW ARTICLE
Marco Toigo · Urs Boutellier
New fundamental resistance exercise determinants of molecular
and cellular muscle adaptations
Accepted: 8 May 2006 / Published online: 15 July 2006
© Springer-Verlag 2006
Abstract Physical activity relies on muscular force. In
adult skeletal muscle, force results from the contraction of
postmitotic, multinucleated myoWbres of diVerent con-
tractile and metabolic properties. MyoWbres can adapt to
(patho-)physiological conditions of altered functional
demand by radial growth, longitudinal growth, and regu-
lation of Wbre type functional gene modules. The adapta-
tion’s speciWcity depends on the distinct molecular and
cellular events triggered by unique combinations of condi-
tional cues. In order to derive eVective and tailored exer-
cise prescriptions, it must be determined (1) which
mechano-biological condition leads to what molecular/
cellular response, and (2) how this molecular/cellular
response relates to the structural, contractile, and meta-
bolic adaptation. It follows that a thorough mechano-bio-
logical description of the loading condition is imperative.
Unfortunately, the deWnition of (resistance) exercise con-
ditions in the past and present literature is insuYcient. It is
classically limited to load magnitude, number of repeti-
tions and sets, rest in-between sets, number of interven-
tions/week, and training period. In this review, we show
why the current description is insuYcient, and identify
new determinants of quantitative and/or qualitative eVects
on skeletal muscle with respect to resistance exercise in
healthy, adult humans. These new mandatory determi-
nants comprise the fractional and temporal distribution of
the contraction modes per repetition, duration of one rep-
etition, rest in-between repetitions, time under tension,
muscular failure, range of motion, recovery time, and ana-
tomical deWnition. We strongly recommend to standardise
the design and description of all future resistance exercise
investigations by using the herein proposed set of 13
mechano-biological determinants (classical and new ones).
Keywords Exercise · Skeletal muscle · Cellular
mechanotransduction · Skeletal muscle satellite cells ·
Hypertrophy
From stimulus to adaptational eVect
Physiological conditions such as resistance exercise per-
turb the skeletal muscle’s tensional integrity (Ingber
2003a, b). These perturbations are mechano-chemically
transduced into a molecular and cellular response within
and between myoWbres and satellite cells (i.e. muscle stem
cells) (Tidball 2005). The mechano-chemical transduction
is based on the genetic background, age, gender, and sev-
eral other factors. Finally, this molecular and cellular
response leads to speciWc structural adaptations that
result in task-speciWc functional enhancement (i.e. the
adaptational eVect) (Fig. 1). However, a causal connection
only exists between the molecular/cellular response (i.e.
signal transduction) and the adaptation (Fig. 1). “More
strength”, i.e. the adaptational eVect, is not necessarily the
result of more muscle mass, since several distinct adapta-
tions can lead to the same eVect (at least in the short
term). Conversely, training in the “6–12-repetition-maxi-
mum zone with multiple sets for 2–3 days week
¡1
”, the so-
called “hypertrophy training” (Kraemer and Ratamess
2004), doesn’t necessarily mean that muscle hypertrophy
(i.e. an increase in muscle mass due to the increase in the
size, as opposed to the number, of preexisting skeletal
muscle Wbres) will result. This is due to the fact that the
ability to exercise is distinct from the ability to adapt. It
has recently been shown for a large cohort of men and
women that signiWcant variability in muscle size and
strength gain exists after unilateral resistance exercise of
the elbow Xexors (Hubal et al. 2005). While some subjects
showed little to no gain, other showed profound changes.
Also, sex diVerences were apparent. Men had a slight
advantage in relative size gains compared to women,
whereas women outpaced men considerably in relative
gains in strength. Age diVerences exhibit a profound
M. Toigo (&) · U. Boutellier
Institute of Human Movement Sciences, and Institute
of Physiology, ETH Zurich, and University of Zurich,
Y23 K 12, Winterthurerstrasse 190, 8057 Zurich, Switzerland
E-mail: mtoigo@biol.ethz.ch
Tel.: +41-44-6355062
Fax: +41-44-6356863
644
impact on the molecular response to resistance exercise,
too (Hameed et al. 2003). Following a single bout of high
load knee extensor resistance exercise, mechanogrowth
factor (MGF) response was attenuated in older subjects.
This is indicative of age-related desensitivity to mechani-
cal loading. Also, various human polymorphisms at
genetic loci have a quantitative eVect on muscle pheno-
type (Thompson et al. 2004). Such polymorphisms, also
known as muscle quantitative trait loci, drive the genetic
variation that underlies muscle size and strength.
Therefore, several prerequisites for the identiWcation
of eVective and speciWc exercise perturbations with
desired functional enhancement are to be met. First,
causal relationships between changes at the molecular
and cellular level and the resulting adaptation need to be
identiWed. These relationships need to be established on
the basis of several factors such as genetics, age, sex, etc.
Further, it must be ascertained whether the adaptation
leads to functional enhancement. Finally, the various
causal connections between signal transduction and
adaptation can be interrogated by multiple exercise
perturbations in order to identify the most eVective and
speciWc exercise perturbations. However, for the identi-
Wcation of eVective and speciWc exercise perturbations it
is imperative to unequivocally deWne and describe the
exercise stimulus in mechano-biological relevant terms.
These mechano-biological terms should be directly asso-
ciated with the molecular response. Unfortunately, in
current investigations into the molecular response to
exercise, perturbation design and deWnition remain
largely undeWned or ignored. This review aims at identi-
fying mechano-biological determinants of exercise
conditions that have quantitative and/or qualitative
eVects on skeletal muscle phenotype. These mechano-
biological determinants are proposed for standardised
description of resistance exercise stimuli in both aca-
demic and recreational settings.
Fundamental mechanical stimuli decoded by skeletal
muscle
Basically, muscles can adopt three strategies of quantita-
tive or qualitative eVect on muscular phenotype to adjust
for altered functional demands (Goldspink 1985): (1)
positive or negative longitudinal growth; (2) positive or
negative radial growth and (3) contractile [myosin heavy
chain (MyHC)] and metabolic tuning. These adaptational
strategies can be adopted concurrently or separately,
depending on the speciWcity of the (patho-)physiological
condition. Generally, exercise-induced physiological con-
ditions can be viewed as the perturbations of the muscle
cells’ tensional integrity. Perturbation of tensional integ-
rity occurs by increasing or decreasing myocellular active
and/or passive tension, as well as energy production or
absorption. Additionally, these tensional and energetic
alterations can be sustained for diVerent duration. Thus,
every exercise condition is coded by a speciWc combina-
tion of changes in constant or intermittent active and/or
passive tension of diVerent duration. These temporal
changes in active and/or passive tension, together with
the inferred structural insults, are then decoded at the
molecular level and transduced into an appropriate
Fig. 1 SimpliWed model for the
transduction of exercise-related
skeletal muscle perturbations
into structural adaptations with
associated adaptational eVect.
An exercise stimulus with deW-
ned mechano-biological charac-
teristics (described in this paper)
(a) is mechano-chemically trans-
duced (c) into a quantitative
and/or qualitative adaptation
(d) of the muscle phenotype,
based on the respective response
matrix (b). The adaptation (d) is
associated with the correspond-
ing adaptational eVect (e). A
causal connection exists be-
tween (c) and (d) (red shading)
m = f(G, Y, S, A, M, T, H, N, I,...)
Genotype (G
)
Age (Y
)
Gender (S
)
Muscular architecture (A
)
Muscular subsystem (M
)
Muscular anthropometry (T
)
Hormonal status (H
)
Nutritional status (N
)
Immunological status (I
)
x
1
...x
i
, mechano-biological exercise
stimulus determinants
e = f(x
1
...x
i
)
s = f(e, m, ...)
a = f(s)
z = f(a)
a
b
c
d
e
exercise stimulus (e)
signal transduction (s)
adaptation (a)
adaptational effect (z)
response matrix (m)
645
adaptational response. In the following sections, we
provide a detailed description on how the three funda-
mental adaptations are regulated at the molecular and
cellular levels. From this, we derive the relevant mec-
hano-biological determinants for resistance exercise-
induced muscular conditioning.
Molecular and cellular determinants of longitudinal
muscle growth
Mechanical measurements of rabbit muscle strips before
and after skinning indicate that total passive tension
increases with increasing sarcomere length (second-order
polynomial) (Prado et al. 2005), i.e. with increased strain.
Total passive tension is believed to develop due to the
lengthening of extramyoWbrillar elements (especially the
collagen content in the extracellular matrix) as well as to
the lengthening of titin. Titin is a giant (» 3–3.7 MDa)
sarcomeric protein that contains a series of spring ele-
ments within its I-band region, which contribute to the
elastic properties of myoWbrils (Prado et al. 2005). Exter-
nal or internal forces applied to the myoWbril lengthen or
shorten the myoWbril to above or below the slack length,
respectively. The lengthening or shortening of the myoW-
bril creates a titin force, which is directed to restore rest-
ing length (Miller et al. 2003). MyoWbrils can be
lengthened actively or passively. This means that myoW-
brils can lengthen while contracting (“lengthening con-
traction”, “eccentric contraction”, “active stretch”) or
without concurrent contraction. In contrast, myoWbrils
can only actively shorten, i.e. while contracting (“short-
ening contraction”, “concentric contraction”). Conse-
quently, passive tension in myoWbrils can develop with or
without concurrent lengthening contraction or with
shortening contraction.
Molecular sensing of myoWbrillar strain
In line with titin’s structural and elastic properties,
mounting evidence indicates that myoWbrillar strain
mediates signalling pathways that involve titin’s Z-line
region (Miller et al. 2003). Signalling pathways comprise
(1) the titin-muscle LIM protein (MLP) pathway, (2) the
N2A-muscle ankyrin repeat protein (MARP) pathway,
and (3) the titin-muscle RING Wnger protein (MuRF)
pathway:
(1) is part of a stretch-dependent myocardial signalling
pathway whose impairment contributes to the patho-
genesis of a subset of dilated cardiomypathies in
humans (Knoll et al. 2002) and is also induced by
skeletal muscle injury due to eccentric exercise
(Barash et al. 2004, 2005; Chen et al. 2002; Hentzen
et al. 2006).
(2) involves 3 homologous MARPs: CARP/MARP1,
Ankrd2/Arpp/MARP2, and DARP/MARP3. MARPs
show cytokine-like induction following cardiac injury,
muscle denervation, and eccentric exercise in vivo
(CARP/MARP1) (Aihara et al. 2000; Barash et al.
2004; Baumeister et al. 1997; Kuo et al.
1999); strain
in culture, immobilisation at stretched muscle length,
and eccentric exercise in vivo (Ankrd2/Arpp/
MARP2) (Barash et al. 2004, 2005; Kemp et al. 2000;
McKoy et al. 2005); or during recovery after meta-
bolic challenge (DARP/MARP3) (Ikeda et al. 2003),
respectively.
(3) is likely to be involved in the regulation of ubiquitin-
proteasome-mediated myoWbrillar protein degrada-
tion (see “Atrophy signalling”). MuRF1 was found
to bind the C-terminal immunoglobulin domains of
titin (Centner et al. 2001), and in the nucleus MuRF1
can bind the transcription factor, glucocorticoid
modulatory element binding protein-1 (McElhinny
et al. 2002). Furthermore, mechanical tension and the
titin catalytic domain have been shown to regulate
the nuclear localisation of MuRF2 and serum
response factor (SRF) (Lange et al. 2005).
Recently, it has also been demonstrated in an in vivo rat
model that CARP and MLP are sensitive to both muscle
tissue stress and contraction mode, while Ankrd2/Arpp
is sensitive only to contraction mode (Barash et al. 2005).
This raises the possibility that strain can be sensed inde-
pendently of stress.
Further evidence for the molecular transduction of
passive tension comes from the » 1.5- and » 2-fold
increase in the serine/threonine kinase Akt [protein
kinase B (PKB)] activity following 5 and 10–20 min of
passive stretch, respectively, of the fast-twitch rat exten-
sor digitorum longus muscle but not in the slow-twitch
soleus muscle (Sakamoto et al. 2003). Once activated,
Akt phosphorylates an array of substrates, including
proteins that mediate protein synthesis, gene transcrip-
tion, cell proliferation, and survival (Vivanco and Saw-
yers 2002). In mammals, there are three forms of Akt,
(Akt1-3), encoded by distinct genes (Vivanco and Saw-
yers 2002). Expression of a constitutively active form of
Akt1 in skeletal muscle cells, either in vitro (Takahashi
et al. 2002) or in mice and rats (Bodine et al. 2001b; Lai
et al. 2004; Pallafacchina et al. 2002), causes hypertro-
phy. Conversely, Akt1 inhibits atrophy in vitro and in
mice (Sandri et al. 2004; Stitt et al. 2004). Based on their
Wnding that passive stretch has no eVect on Akt activity
in rat slow-twitch soleus muscle (in contrast to rat
extensor digitorum longus muscle), the authors sug-
gested that susceptibility to mechanical stretch is Wbre
type-speciWc (Sakamoto et al. 2003). This notion is also
supported by the recent Wnding that the relative impor-
tance of titin and the extracellular matrix for total pas-
sive tension can vary between diVerent adult rabbit
skeletal muscles (Prado et al. 2005). Slow-twitch rabbit
muscles exhibit low titin-based passive tension but this
tension is highly variable in fast-twitch muscles. Fur-
thermore, titin-based passive tension, but not extramyo-
Wbrillar passive tension correlates with the muscle type
(Prado et al. 2005).
646
Cellular sensing of mechanical stretch
Satellite cells are muscle precursor cells that lie between
the basal lamina and sarcolemma of skeletal muscle
Wbres (Mauro 1961). In normal adult muscle, satellite
cells are mitotically and metabolically quiescent (Schultz
et al. 1978). With appropriate environmental signals, sat-
ellite cells enter into the cell cycle, i.e. are “activated”, to
provide the precursors needed for new muscle formation
in growth and repair (Charge and Rudnicki 2004; Hill
et al. 2003; McKinnell et al. 2005). Results from in vitro
stretch assays demonstrate that mechanical stretch can
result in satellite cell activation (Anderson 2000; Ander-
son and Pilipowicz 2002; Tatsumi et al. 2001; Wozniak
et al. 2003). This mechanical stretch induces hepatocyte
growth factor (HGF) release from its tethering in the
extracellular matrix in a nitric oxide-dependent manner
(Tatsumi and Allen 2004; Tatsumi et al. 2002). Once
released, HGF binds to the c-met receptor which is
located on the plasma membrane of the satellite cells.
This interaction initiates a cascade of signalling events
that lead to DNA synthesis, and, thus, to satellite cell
proliferation.
Structural adaptation to strain perturbation
It has long been known that muscles adapt to a new
functional length by adding or removing sarcomeres in
series at the ends of the existing myoWbrils (Dix and
Eisenberg 1990; GriYn et al. 1971; Tabary et al. 1972;
Williams and Goldspink 1971). Immobilisation at long
muscle length results in an increase in the number of sar-
comeres in series. Conversely, immobilisation at short
muscle length leads to a decrease in the number of sarco-
meres in series. Furthermore, remodelling of the connec-
tive tissue following immobilisation has been
demonstrated multiple times in mice, rats, rabbits, and
cats (Goldspink 1985; Tabary et al. 1976; Tardieu et al.
1977, 1982; Williams and Goldspink 1984). However,
both the occurrence and the extent of remodelling seem
to depend on the connective tissue type (series elastic ele-
ment and/or parallel elastic element), species, age, muscle
length during immobilisation, and time period of immo-
bilisation.
In exercise physiology, serial sarcomere number mod-
ulation has been a neglected topic so far (Morgan and
Proske 2004). Only recently has serial sarcomere number
modulation been investigated in the context of exercise.
Direct evidence for exercise-induced modulation of serial
sarcomere number has come from treadmill-trained rat
vastus intermedius muscles, the postural knee extensors
(Lynn and Morgan 1994; Lynn et al. 1998). Rats were
trained by running on a climbing or descending treadmill
for approximately 10 min day
¡1
for 5 days. The latter
had previously been shown to cause muscle damage.
Subsequently, serial sarcomere analysis for single Wbres
was performed by laser diVraction. As a result, the
descending-trained rats had the largest sarcomere count,
the climbing-trained rats had the smallest count, and
sedentary rats had intermediate counts, although closer
to the climbing group. In another series of experiments,
rat vastus intermedius muscles were tested mechanically
while still in situ, i.e. attached to the bones, but with all
other muscles about the knee joint removed. As a result,
in descending-trained rats, the knee angle for optimum
torque generation corresponded to longer muscle lengths
than in climbing-trained rats. It follows from these
results that eccentric exercise (lengthening contractions)
leads to accretion of serial sarcomeres. Conversely, exer-
cise comprising only shortening contractions leads to a
decrease in the number of serial sarcomeres. Due to the
Wnding that 38% of the diVerence in sarcomere numbers
between decline- and incline-trained rats does not appear
as a diVerence in optimum angle, the authors suggest
that it has been taken up by shortened tendons (Lynn
et al. 1998).
Recently, the contraction type-dependent diVerential
serial sarcomere number adaptation has been conWrmed
by measuring vastus intermedius and vastus lateralis
muscle Wbre dynamics of up- and downhill-running rats
in vivo (ButterWeld et al. 2005). It was shown in that
study that vastus intermedius and vastus lateralis mus-
cles of uphill-walking rats undergo repeated concentric
contractions, and therefore they suVer no contraction-
induced injury. Conversely, the vastus intermedius and
vastus lateralis muscles during downhill walking
undergo repeated eccentric contractions (ButterWeld
et al. 2005). Accordingly, short muscle lengths for uphill
concentric-biased contractions result in a loss of serial
sarcomeres, while long muscle lengths for downhill
eccentric-biased contractions result in a gain of serial
sarcomeres (ButterWeld et al. 2005).
In humans, the optimum angle for torque generation
can be measured reliably, e.g. by isokinetic dynamome-
try. By that means, an angle-torque curve is measured
during maximum voluntary contraction with constant
velocity shortening. As determined by this measure, a
series of eccentric contractions (“hamstring lowers”) of
human hamstring muscles produced a signiWcant shift of
approximately 7° in optimum knee angle for torque gen-
eration to longer muscle lengths (Brockett et al. 2001).
The shift in optimum knee angle for torque generation
was parallelled by delayed-onset muscle soreness
(DOMS) in the hamstrings. The shift occurred immedi-
ately after exercise and persisted 8 days postexercise,
consistent with a training eVect. The mechanism by
which eccentric exercise produces muscle damage,
DOMS, and increased optimum length for torque gener-
ation has been postulated in the “popping sarcomere
hypothesis” (Morgan 1990
). The popping sarcomere
hypothesis states that stretch-induced muscle damage
results from nonuniform lengthening of sarcomeres,
when active muscle is stretched beyond optimum length.
If sarcomeres are beyond optimum length, then the lon-
gest sarcomeres will be the weakest and, so, will be
stretched more rapidly than the others. Thus, they will
become weaker, until rising passive tension compensates
for falling active tension. For at least some muscles this
647
corresponds to lengths beyond Wlament overlap. The
term “popping” is used to describe the uncontrolled, vir-
tually instantaneous lengthening of a sarcomere from a
length commensurate with its passive length to a length
where passive structures primarily support the tension.
Because the weakest sarcomeres are not at the same
point along each myoWbril, this nonuniform lengthening
leads to a shearing of myoWbrils, exposing membranes,
especially T-tubules, to large deformations. This is
thought to lead to loss of Ca
2+
homeostasis, and, hence,
damage, either through tearing of membranes or open-
ing of stretch-activated channels (Allen et al. 2005). Sup-
port for the nonuniform lengthening of sarcomeres
comes from a recent study of myoWbrils from rabbit
psoas muscle and left ventricles of guinea pig during acti-
vation and relaxation (Telley et al. 2006a). However,
these authors also show that albeit half-sarcomeres of
contracting single rabbit psoas myoWbrils lengthen to
diVerent extents during a stretch, rapid elongation of
individual sarcomeres beyond Wlament overlap (pop-
ping) does not occur. Moreover, in contrast to predic-
tions of the popping sarcomere hypothesis, they
postulate that a stretch rather stabilises the uniformity of
half-sarcomere lengths and sarcomere symmetry (Telley
et al. 2006b).
With respect to eccentric exercise, it is postulated that
the structural adaptation consists of an increase in the
number of sarcomeres in series so that a given muscle
length corresponds to a shorter sarcomere length (Mor-
gan and Talbot 2002). Whether and how serial sarco-
mere adaptation in humans following eccentric exercise
is parallelled by changes in tendinous and/or muscle
belly connective tissue remains to be established.
A consequence of the popping sarcomere hypothesis
is that the unloaded shortening velocity of muscle Wbres
should increase with eccentric training. The reason for
this is that the unloaded shortening velocity of a Wbre is
the sum of the velocities of its sarcomeres. Thus, the
more sarcomeres in series, the faster the unloaded short-
ening velocity, provided that no alterations in MyHC
composition occur. However, this will have to be demon-
strated in future experiments, especially with respect to
the MyHC isoform gene switching associated with
stretch and force production (Goldspink et al. 1991).
Another consequence of the popping sarcomere hypoth-
esis is that signiWcant muscle damage also can occur with
endurance exercise, provided that the duration (mara-
thon running) or mode (downhill running) of exercise is
extreme. Therefore, it is predicted that under certain cir-
cumstances, endurance exercise can lead to serial sarco-
mere accretion with concurrent increase in unloaded
Wbre shortening velocity. On the contrary, “conven-
tional” endurance exercise, which is associated with a
bias towards shortening contractions at short muscle
lengths, will lead to a decrease in the serial sarcomere
number and, thus, to shorter muscle lengths. Short mus-
cle lengths come with a reduction in functional range of
motion (ROM). In general, a reduction in ROM is not
desirable in health-based settings that aim at increasing
musculoskeletal and cardiovascular function. Hence, in
order to increase or preserve a functional ROM by serial
sarcomere number modulation, eccentric resistance exer-
cise covering the functional articular range might be the
method of choice.
In conclusion, there is a substantial body of evidence
that muscle Wbres and satellite cells can sense changes in
length. Accordingly, active and passive excursions from
resting length are transduced into a molecular and cellu-
lar response with subsequent structural adaptation. How-
ever, with respect to active excursions from resting length,
the response at the molecular, cellular, and structural
level is dependent on the contraction mode. It follows
directly that muscle length change as well as contraction
mode are two mechano-biological determinants of exer-
cise-induced skeletal muscle length adaptation. Therefore,
these two mechano-biological determinants, among oth-
ers (described below), need to be speciWed in reports com-
ing from investigations into the plasticity of skeletal
muscle following (resistance) exercise. As a measure of
muscle length change we suggest to specify ROM (x
11
,
Table 1) during exercise and the number of length excur-
sions [i.e. the number of repetitions (x
2
, Table 1)]. It must
be pointed out, however, that ROM might not always be
indicative of fascicle length excursion. The reason for this
is that length changes of the muscle-tendon units do not
necessarily correspond to the length changes in the mus-
cle fascicles (Hoyt et al. 2005). This means that the mus-
cle-tendon-unit may lengthen, while the contracting
muscle is shortening or isometric. As a measure of con-
traction mode we propose to report the fractional distri-
bution of the three contraction types [shortening
(concentric), isometric, lengthening (eccentric)] per repeti-
tion in terms of occurrence and temporal requirement (x
7
,
Table 1). Also, the number of contractions should be
reported (x
2
and x
3
, Table 1). For example, did the exer-
cise comprise one set of several, only lengthening contrac-
tions or was one repetition composed of one shortening,
one isometric, and one lengthening contraction? How
much time did it take to perform one repetition and how
was this time distributed over the respective contraction
modes? The importance of the latter point for inducing
muscle hypertrophy and gains in strength has been dem-
onstrated in studies where the eVect of fast lengthening
contractions versus slow lengthening or slow shortening
contractions has been investigated (Farthing and Chili-
beck 2003; Shepstone et al. 2005).
Molecular and cellular determinants of radial muscle
hypertrophy
Previous work showed that if the tibialis anterior in the
mature rabbit was electrically stimulated while held in
the stretched position by plaster cast immobilisation, it
increased in mass by 35% within 7 days (Goldspink et al.
1992). Thus, if the lengthened (stretched) rodent muscle
is additionally subjected to electrical stimulation, it
648
increases in girth as well as length. The distinct role of
active tension in generating radial growth is evidenced
by this Wnding. Conversely, when muscle contractile
activity is reduced by means of immobilisation (e.g. cast-
ing) or unloading (bed rest, space Xight), rapid muscle
loss (atrophy) occurs (Booth and Kelso 1973; Thomason
and Booth 1990). Muscle loss is accentuated when immo-
bilisation occurs at short muscle length and attenuated
when immobilisation occurs at long muscle length, i.e. in
a stretched position (Dupont Salter et al. 2003). There-
fore, muscle growth and muscle atrophy are two oppos-
ing phenomena that are mechanistically linked. Either
the activity or inactivity of a common set of molecules
controlling a few cellular pathways determines whether
the skeletal muscle tissue will respond to deWned stimuli
with increased protein synthesis and stimulation of cell
growth or with increased protein breakdown and
reduced cell proliferation (Glass 2003a, b, 2005; Nader
2005; Rennie et al. 2004; Sartorelli and Fulco 2004). In
essence, the maintenance of skeletal muscle mass is the
result of the dynamic balance between muscle protein
synthesis and muscle protein degradation. Thus, these
two opposite processes are believed to hold the key to
the understanding of the mechanisms involved in the reg-
ulation of skeletal muscle mass.
Resistance exercise in humans and relevant animal
models such as functional overload via synergist abla-
tion can produce a signiWcant increase in the mass of the
overloaded muscles. In contrast to endurance exercise,
resistance exercise is associated with high-intensity-
short-duration workloads. The high-intensity-short-
duration workloads placed on skeletal muscle during
resistance exercise are at or near maximal capacity, and
as such produce signiWcant perturbations to the skeletal
muscle Wbres and the associated extracellular matrix.
These perturbations can lead to signiWcant muscle dam-
age, especially if lengthening contractions (eccentric
exercise) with supramaximal loads are performed. How-
75% 1RM 6 1
x
13
shortening
isometric
lengthening
no
0 s
2 s
2 s 24+5 s no 60% 24 h
75% 1RM 6 shortening
isometric
lengthening
yes
2 s
4 s
10 s 96+10 s yes 100%
72 h
x
1
x
7
x
6
x
2
x
9
x
10
x
11
x
4
x
12
x
3
2 per week
10 weeks
x
5
1
-
-
A
B
b
a
x
1
, load magnitude
x
7
, fractional and temporal distribution of the contraction
modes per repetition and duration [s] of one repetition
x
6
, duration of the experimental period ([d] or weeks)
x
2
, number of repetitions
x
9
, time under tension ([s] or [min])
x
10
, volitional muscular failure
x
11
, range of motion
x
4
, rest in-between sets ([s] or [min])
x
12
, recovery time in-between exercise sessions ([h] or [d])
x
3
, number of sets
x
5
, number of exercise interventions (per [d] or week)
x
13
, anatomical definition of the exercise (exercise form)
New set of descriptors Classical set of descriptors
Complete set of mechano-biological descriptors
x
8
, rest in-between repetitions ([s] or [min])
x
8
-
-
2 per week
10 weeks
Table 1 Mechano-biological descriptors of resistance exercise stim-
uli. In order to better discriminate between the signiWcant stimula-
tory cues leading to distinct muscular adaptations, we propose to
design and describe resistance exercise-related muscular perturba-
tions based on mechano-biological descriptors (a). Example of how
inaccurate exercise stimulus description might lead to wrong conclu-
sions (b). Based on the traditional resistance exercise descriptors (x
1
-
x
6
), two hypothetical subjects (denoted A and B) receive exactly the
same resistance exercise stimulus. However, when further missing
mechano-biologically signiWcant descriptors (x
7
-x
13
) are taken into
account, it is obvious that the two conditions diVer. These two diVer-
ring conditions will lead to distinct mechano-chemical signal trans-
ductions in the subjects’ muscles, even if the two subjects had the
same potential to adapt (i.e. the same response matrix characteristics
[see Fig. 1]). Thus, the two diVerring mechano-chemical signal trans-
ductions will most likely lead to distinct muscular adaptations and
adaptational eVects. Consequently, such results could be misinter-
preted
649
ever, while both resistance and endurance exercise can
result in muscle injury, resistance exercise is more likely
to be associated with increases in Wbre cross-sectional
area and mass. The reasons for the response’s speciWcity
point to diVerences in the integration of hormonal, meta-
bolic, mechanical, neuronal, and immune responses,
which are all likely involved in the distinct transcrip-
tional responses that characterise endurance and resis-
tance training.
Molecular determinants of skeletal muscle hypertrophy
and atrophy
Exercise-induced hypertrophy mediators upstream of Akt
Resistance exercise-induced muscle hypertrophy results
when muscle protein synthesis exceeds muscle protein
degradation. In contrast, muscle atrophy is the result
from increased muscle protein degradation over muscle
protein synthesis. The integration of both anabolic and
catabolic signals that lead to the increase or decrease in
skeletal muscle mass (Fig. 2) is believed to occur at the
molecular nodal point Akt (Nader 2005). Thus, activated
(phosphorylated) Akt is both an eVector of anabolic sig-
nals and a dominant inhibitor of catabolic signals. Acti-
vation of Akt is mediated by the insulin-like growth
factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)
pathway. The IGF-1/PI3K pathway is triggered by
increased muscle loading and subsequent expression of
the gene encoding IGF-1 in both animal models (DeVol
et al. 1990) and humans (Bamman et al. 2001). On the
basis of their mRNA transcripts, three human muscle
IGF-1 isoforms have been identiWed so far: IGF-1Ea
(“liver type” isoform), IGF-1Eb, and IGF-1Ec (MGF)
(Goldspink 2005; Hameed et al. 2003). In overloaded
rodent muscle there are two clearly identiWed transcripts,
IGF-1Ea and IGF-1Eb, of which IGF-1Eb has been
termed MGF (Goldspink 2005). Rodent MGF diVers
slightly from the human MGF sequence as it contains a
52 base pair insert in exon 5 (Goldspink 2005). Other
terms such as “mIGF-1”, which corresponds to the IGF-
1Ea isoform, have also been used to describe the diVerent
isoforms (Musaro et al. 2001). However, only MGF
appears to be activated by mechanical signals (Yang
et al. 1996).
These muscle-speciWc isoforms of IGF-1 are believed
to be suYcient to induce hypertrophy through either
autocrine or paracrine mechanisms (DeVol et al. 1990).
Transgenic mice engineered to overexpress systemic or
liver type IGF-1 under the control of a muscle-speciWc
promoter have skeletal muscles that are twofold greater
in mass than those seen in normal mice (Coleman et al.
1995; Musaro et al. 2001). Binding of the cytokine IGF-1
induces a conformational change in the muscle IGF-1
receptor (IGFR) tyrosine kinase, resulting in its
trans-
phosphorylation and the subsequent phosphorylation of
insulin receptor substrate 1 (IRS-1). In turn, this results
in the activation of PI3K. Finally, activation of PI3K
results in the production of phosphatidylinositol-3,4,5-
triphosphate and activation of Akt via 3⬘-phosphoinosi-
tide-dependent protein kinase 1 (PDK1). However,
whether IGF-1 acts as an extracellular cue in muscle
biology depends on its availability for muscle IGFR.
Indeed, the availability of IGF-1 for muscle IGFR is
controlled by IGF-1-binding proteins (IGFBPs). Binding
of IGF-1 to IGFBPs can lead either to stimulation or
inhibition of IGF-1 eVects.
Hypertrophy mediators downstream of PI3K and Akt
Two pathways downstream of PI3K and Akt are
believed to mediate hypertrophy (Glass 2005; Nader
2005): the Akt/mammalian target of rapamycin (mTOR)
pathway, and the Akt/glycogen synthase kinase 3 beta
(GSK3) pathway. Both pathways lead to marked
hypertrophy through activation of the protein synthetic
machinery. Activation of mTOR by phosphorylated Akt
Fig. 2 SimpliWed model for the relationship between muscle Wbre
size and the balance between anabolic and catabolic stimuli. Muscle
size (girth and/or length) is set by the balance between activity-in-
duced hypertrophy (anabolic) (blue) and counteracting atrophy
(catabolic) (red) signals. In normal muscle, subjected to some
amount of tear and wear, hypertrophy and atrophy signals are in
balance (a). Resistance exercise perturbs the balance by inducing
hypertrophy signals over atrophy signals (b), or by inhibiting atro-
phy signals (c), or both (d), thus driving hypertrophy. This model
does not take into account changes in the contractile and metabolic
proWle that may occur following resistance exercise
Hypertrophy signalling Atrophy signalling
Hypertrophy signalling
Atrophy signalling
Hypertrophy signalling
Atrophy signalling
Hypertrophy signalling
Atrophy signalling
Set muscle
girth/lengt
h
a
b
c
d
Muscle size
Set muscle
girth/length
Set muscle
girth/length
Set muscle
girth/length
650
results in an increase in protein translation by two mech-
anisms: Wrst, mTOR activates 70 kDa ribosomal S6 pro-
tein kinase (S6K1/p70
S6k
), a positive regulator of protein
translation; second, mTOR inhibits the activity of
PHAS-1 (also known as 4E-BP1), a negative regulator of
the protein initiation factor eIF-4E. Conversely, phos-
phorylation of Akt results in the inactivation of GSK3.
GSK3 blocks protein translation initiated by the eIF2B
protein. Therefore, GSK3 inhibition may induce hyper-
trophy by stimulating protein synthesis independent of
the mTOR pathway.
Other growth-signalling pathways in skeletal muscle
Other signal transduction pathways shown to be acti-
vated in response to various forms of muscle contraction
include those involving the mitogen-activated protein
kinase (MAPK) signalling pathways (Long et al. 2004).
The MAPK-signalling pathways constitute a network of
phosphorylation cascades that link cellular stress to
changes in transcriptional activity. Relevant to the pres-
ent review is the observation that exercise leads to the
activation of at least three MAPK-signalling pathways,
i.e. extracellular signal-regulated kinases (ERK)1/2, p38
MAPK, c-JUN NH
2
-terminal kinase (JNK), in skeletal
muscle (Aronson et al. 1998; Boppart et al. 1999; Wide-
gren et al. 2000). Further, AMP-activated protein kinase
(AMPK) activity has been shown to be increased during
contractions and exercise both in rodents and humans
(Winder 2001). However, the relevance of the AMPK-
signalling pathway has recently been questioned (Brooks
2005; Wadley et al. 2006). With respect to calcineurin sig-
nalling in working skeletal muscle, the reader is referred
to chapter “Molecular and cellular determinants of con-
tractile and metabolic tuning”.
Atrophy signalling
As with protein synthesis, degradation of cellular pro-
teins is an essential process for the maintenance of myo-
cellular homeostasis. However, in some speciWc
situations, when protein degradation exceeds protein syn-
thesis, skeletal muscle mass loss occurs. This process of
mass loss is termed atrophy. Skeletal muscle atrophy is a
serious consequence of various conditions such as micro-
gravity, hindlimb suspension, immobilisation, and
numerous diseases, including cancer and AIDS (Baracos
2001; Booth and Kelso 1973; Miro et al. 1997; Thomason
and Booth 1990). Muscle loss is parallelled by profound
transcriptomic (Bey et al. 2003; Cros et al. 2001; St-
Amand et al. 2001; Stein et al. 2002; Stevenson et al.
2003; Wittwer et al. 2002) and proteomic (Isfort et al.
2000, 2002a, b; Toigo et al. 2005) changes. Over the years,
several studies have identiWed at least Wve diVerent sys-
tems involved in the degradation of proteins during mus-
cle atrophy (Jackman and Kandarian 2004; Kandarian
and Jackman 2006). These are the lysosomal system, the
calpain system, the caspase or apoptotic protease system,
the ubiquitin proteasome system, and the nuclear factor
kappa B (NF-B) system. At present, it remains unclear
what the relative contribution of these systems to the
atrophy process are, and which speciWc roles they may
play during each particular disease state or context in
which muscle atrophy develops. However, among the
various systems involved in muscle proteolysis during
atrophy, the ubiquitin-proteasome system is thought to
play a major role (Jagoe et al. 2002). In addition to ubiq-
uitin, three distinct enzymatic components are required,
an E1 ubiquitin-activating enzyme, an E2 ubiquitin-con-
jugating enzyme, and an E3 ubiquitin-ligating enzyme
(Glickman and Ciechanover 2002). The E3 ubiquitin
ligases are the components which confer substrate speci-
Wcity. In multiple models of skeletal muscle atrophy, the
expression levels of two genes increased signiWcantly:
Muscle Ring Finger 1 (MuRF1) (Bodine et al. 2001a) and
Muscle Atrophy F-box (MAFbx) (Bodine et al. 2001a)
[also called Atrogin-1 (Gomes et al. 2001)]. Both MuRF1
and MAFbx/Atrogin were shown to encode E3 ubiquitin
ligases and to be speciWcally expressed in skeletal muscle
(Bodine et al. 2001a). However, the upregulation of
MuRF1 and MAFbx/Atrogin requires the nuclear trans-
location and activity of a family of transcription factors
termed Forkhead box O (FOXO). Indeed, in the context
of skeletal muscle atrophy, an increase in FOXO1
mRNA in addition to several other atrophy-related genes
was reported (Lecker et al. 2004). Also, FOXO3 activa-
tion was demonstrated to be suYcient to induce atrophy
(Sandri et al. 2004). However, recent evidence shows that
FOXO transcription factors are excluded from the
nucleus when phosphorylated by Akt, and translocate to
the nucleus upon dephosphorylation. Thus, muscle atro-
phy is prevented by FOXO inhibition through nuclear
exclusion by phosphorylation through Akt. This Wnding
highlights Akt’s role as a molecular checkpoint for the
integration of both anabolic and catabolic signals that
lead either to the increase or decrease in skeletal muscle
mass. However, although there is a distinct set of genes
which are inversely regulated by hypertrophy and atro-
phy (Latres et al. 2005), distinct transcriptional pathways
are activated in skeletal muscle atrophy. These distinct
transcriptional pathways are not necessarily the converse
of those seen during hypertrophy. Thus, it seems that
atrophy is not simply the converse of hypertrophy.
Muscle mass enhancement by inhibition
of negative regulators
Myostatin, also known as growth and diVerentiation
factor 8 (GDF-8), is a transforming growth factor–
(TGF-) family member. It inhibits the progression of
myoblasts from G1- to S-phase of the cell cycle through
upregulation of p21, the only cyclin-dependent kinase 2
(Cdk2) inhibitor (McCroskery et al. 2003). Myostatin
also inhibits myoblast diVerentiation by downregulation
of MyoD/Myogenin expression (Langley et al. 2002).
Consequently, myostatin acts as a negative regulator of
skeletal muscle mass in (1) cattle, (2) mice, and (3)
humans. (1) Naturally occurring mutations in the myo-
651
statin gene are responsible for the “double-muscling”
phenotype, which is characterised by a dramatic
increase in muscle mass of certain breeds of cattle
(McPherron and Lee 1997). (2) Myostatin-null mice
show an increase in muscle mass due to muscle hyper-
plasia and hypertrophy (McPherron et al. 1997). (3)
Recently, a child with muscle hypertrophy was found to
have a loss-of-function mutation in the myostatin gene
(Schuelke et al. 2004). This individual showed a quadri-
ceps cross-sectional area 7.2 standard deviations above
the mean for age- and sex-matched controls and the
ability to hold two 3 kg dumbbells in “horizontal sus-
pension with arms extended” at the age of 4.3 years
(Schuelke et al. 2004). As suggested, other less dramatic
changes in the myostatin gene (or heterozygosity for the
splice site mutation) may confer enhanced athletic
prowess in a less conspicuous manner (McNally 2004).
However, the child’s mutation has not been found in
any other individual, and is therefore not a polymor-
phism-driving normal human variation (Gordon et al.
2005). Furthermore, genetic association studies with
myostatin polymorphisms have consistently failed to
demonstrate any statistically signiWcant relationship
with any human muscle trait (Ferrell et al. 1999; Ivey
et al. 2000; Thomis et al. 2004).
In summary, skeletal muscle mass depends on the
dynamic balance of protein synthesis versus protein
breakdown. Whether muscle Wbre protein synthesis out-
weighs protein degradation depends on the activity of
intracellular hypertrophy- and atrophy-inducing media-
tors (Fig. 2). The activity of intracellular hypertropy- and
atrophy-inducing mediators is coordinated at molecular
checkpoints within the myoWbre. These molecular check-
points integrate anabolic and catabolic signals that are
triggered by (patho-)physiological conditions. Resistance
exercise is a physiological condition that aims at induc-
ing hypertrophy signalling while repressing atrophy sig-
nalling (Fig. 2), Wnally leading to myoWbre hypertrophy.
Resistance exercise is associated with high active tension
that is imposed on skeletal muscle. As shown, active ten-
sion through muscular contraction is per se a potent ana-
bolic stimulus for myoWbre hypertrophy. However, the
levels of active tension required to induce graded hyper-
trophic eVects or to prevent atrophy are most likely to
diVer. Therefore, such graded tensional eVects must be
investigated at the molecular and cellular level, if speciWc
exercise regimens, e.g. for the prevention or treatment of
sarcopenia, are to be developed. Consequently, the level
of active tension that is imposed on skeletal muscle dur-
ing resistance exercise is a further signiWcant mechano-
biological determinant of skeletal muscle size adaptation
(x
1
, Table 1). As such, it should be quantiWed in resis-
tance exercise reports. However, the quantiWcation of the
load magnitude poses some problems, since usually, load
magnitude is reported in terms of the one-repetition-
maximum (1RM), e.g. 75% 1RM. It is beyond the scope
of this review to discuss issues related to the 1RM.
SuYce it to say that in a scientiWc setting we do not con-
sider the 1RM an appropriate measure to determine the
magnitude of the tensional load for exercise. In a scien-
tiWc setting, we suggest to construct maximal voluntary
torque (MVT)-angle curves, whenever possible. Based on
these MVT-angle curves, the respective choices with
respect to tension magnitude can be legitimated. More-
over, MVT intramuscular imbalances (joint angles of
disproportionate torque) can be detected and pre-/post-
MVT-angle curves can be compared with respect to
MVT as well as optimum angle for torque generation
(
see “Structural adaptation to strain perturbation”). In
most other settings it might be more practical to report
the load magnitude in terms of 1RM [e.g. % 1RM (x
1
,
Table 1)]. Importantly, information about the 1RM
should always be combined with information about the
time under tension (TUT) (x
9
, Table 1) until failure. That
is, how many seconds the exercise can maximally be sus-
tained prior to volitional failure (x
10
, Table 1). This will
additionally give important information about the meta-
bolic changes occurring with training (see “Molecular
and cellular determinants of contractile and metabolic
tuning”). However, load magnitude per se is not a mea-
sure of muscular loading. Only an anatomically perfect
technique will allow the eYcient “delivery” of the load to
the muscle under investigation. It follows that a sound
anatomical deWnition of the exercise in terms of joint
positions, movement velocity (movement control), etc.
should be an integral part of the exercise stimulus
descriptions (x
13
, Table 1). It is imperative to know if the
muscle was under permanent tension and how much of
the load eVectively “reached” the target muscle.
Cellular determinants of muscle hypertrophy
and atrophy
As mentioned above, satellite cells are lineage-commit-
ted adult muscle stem cells, located between the basal
lamina and the sarcolemma of myoWbres. Satellite cells
contribute to postnatal muscle growth and muscle
regeneration after injury (Charge and Rudnicki 2004;
Dhawan and Rando 2005; McKinnell et al. 2005;
Wagers and Conboy 2005). Upon myotrauma, quiescent
satellite cells become activated, proliferate, and ulti-
mately fuse to existing damaged muscle Wbres or among
themselves to form new myoWbres. Satellite cells are
activated in response to hypertrophic stimuli, such as
those occurring during muscle mechanical overload
(Darr and Schultz 1987; Moss and Leblond 1971; Schi-
aVino et al. 1976). In several animal models of compen-
satory hypertrophy (Hanzlikova et al. 1975; Snow 1990)
or after resistance training in humans (Kadi et al. 1999a,
b, 2004; Roth et al. 2001), the total number of activated
satellite cells is substantially increased. The mechanisms
leading to satellite cell activation during muscle hyper-
trophy are not entirely understood. It is postulated that
extensive physical activity, such as resistance training or
muscle overloading (chronic stretch, agonist muscle
ablation, tenotomy), inXicts muscle injury (Allen et al.
2005; Armstrong et al. 1991; Faulkner et al. 1993;
Gibala et al. 1995). Consequently, muscle injury, similar
652
to more severe muscle damage, may initiate a process of
regeneration. An indirect proof of muscle damage after
mechanical stress is given by an increase of serum mark-
ers such as muscle creatine kinase, an enzyme that is
usually restricted to the myoWbre cytosol. Muscle injury
initiates an inXammatory response with the attraction of
nonmuscle mononucleated cells, such as neutrophils and
macrophages, into the damaged zone (Fielding et al.
1993). Subsequently, several growth factors are released
either by the inWltrating cells or by the damaged myoW-
bres themselves. These growth factors may ultimately
regulate satellite cell proliferation and diVerentiation.
Indeed, several cytokines have been described that mod-
ulate proliferation and diVerentiation of satellite cells in
vitro or during regeneration after (exercise-induced)
muscle injury (Charge and Rudnicki 2004; Vierck et al.
2000). As mentioned above, HGF is considered to be a
key regulator of satellite cell activity during muscle
regeneration (Allen et al. 1995; BischoV 1997). HGF is
secreted by damaged tissue during the early phase of
muscle regeneration in amounts proportional to the
extent of muscle injury (Sheehan and Allen 1999; Tats-
umi et al. 1998). It seems that HGF directly regulates
satellite cell activation. As described, a large body of evi-
dence supports the importance of IGF-1 in the genesis
of skeletal muscle hypertrophy. IGF-1 can promote
both proliferation and diVerentiation of cultured satel-
lite cells, and these Wndings have been conWrmed in ani-
mal models (Charge and Rudnicki 2004). Experiments
showed that muscle-localised expression of IGF-1Ea
(“mIGF-1”) prevented, through an increase of the
regenerative potential of satellite cells, the age-related
loss of muscle mass (Musaro et al. 2001). Also, satellite
cells derived from mice overexpressing IGF-1Ea display
an increased proliferative potential (Chakravarthy et al.
2000b). Increased proliferative potential seems to be
mediated by activation of the IGF-1/PI3K/Akt path-
way, which results in the inactivation (phosphorylation)
of FOXO1 (Machida et al. 2003). Inactivation of
FOXO1 downregulates the activation of the p27
Kip1
promoter (Chakravarthy et al. 2000a). Therefore, the
molecular pathways activated by IGF-1 in the muscle
Wbres to promote increased protein translation appear
also to be activated in satellite cells. However, IGF-1
action on satellite cells seems to be IGF-1 isoform-spe-
ciWc with apparently diVerent expression kinetics
(Goldspink 2005). After exercise and/or damage, the
IGF-1 gene is Wrst spliced towards MGF but after a day
or so becomes completely spliced towards the systemic
IGF-1 isoforms, which in human muscle are IGF-1Ea
and IGF1-Eb (Goldspink 2005; Haddad and Adams
2002; Hill and Goldspink 2003; Hill et al. 2003; Yang
and Goldspink 2002).
Concepts of myocellular enlargement
Muscle Wbres, i.e. multinucleated muscle cells, develop
during embryonic diVerentiation, when mononucleated
myoblasts Wrst proliferate and then fuse to form myotu-
bes that become innervated. Following myoblast fusion,
no further mitotic divisions occur within the myotubes
or muscle Wbres. Thus, under normal biological condi-
tions, adult skeletal muscle is an extremely stable tissue
with little turnover of nuclei (Decary et al. 1997; Sch-
malbruch and Lewis 2000). These Wndings about the
postmitotic and multinucleated nature of muscle Wbres
have led to the concept of a DNA unit or myonuclear
domain (Allen et al. 1999; Cheek 1985; Hall and Ralston
1989). The myonuclear domain is the theoretical amount
of cytoplasm supported by a single myonucleus. How-
ever, the concept of a myonuclear domain is a theoretical
one since regulation of the expression and distribution of
individual proteins within the muscle Wbre is dependent
on a number of diVerent variables related to the nature
of each protein. Nonetheless, since each muscle Wbre is
made up of many myonuclear domains, muscle Wbre
radial or longitudinal hypertrophy could conceivably
result from either an increase in the number of domains
(by increasing myonuclear number) or by an increase in
the size of existing domains (Edgerton and Roy 1991)
(Fig. 3). Research to date has strongly supported the
former concept by showing that satellite cell activation is
required for muscle hypertrophy. The requirement of
satellite cell activation was Wrst demonstrated by an
approach in which mild
-irradiation was employed to
block satellite cell proliferation. In response to functional
overload, myonuclear number or muscle size was not
increased in irradiated rat and mice muscles (Adams
et al. 2002; Rosenblatt and Parry 1992). However, recent
reports indicate that the size of myoWbres can increase
without the addition of new myonuclei (Kadi et al. 2004;
Wada et al. 2003; Zhong et al. 2005). It was found that
following 30 and 90 days of resistance exercise, the Wbre
area controlled by each myonucleus gradually increased
throughout the training period and returned to pretrain-
ing values during detraining (Kadi et al. 2004). No alter-
ations in the number of myonuclei were detected.
Moreover, it has been shown that under normal physio-
logical conditions myonuclear domain size might vary
throughout mouse lifespan (Wada et al. 2003) and that
myonuclear domain size is not constant during rat soleus
muscle atrophy (Zhong et al. 2005).
Whether the increase in mass during hypertrophy
results from an increase in the size of each Wbre (hyper-
trophy) or by an increase in Wbre number (hyperplasia),
has been under debate. Although the evidence has been
somewhat contradictory, there has been some suggestion
that an increase in Wbre number may occur in some ani-
mals under certain experimental conditions. Indeed, a
review of several investigations into skeletal muscle
growth concluded that in several animal species certain
forms of mechanical overload increases muscle Wbre
number (Kelley 1996). However, it has been suggested
that some reports have misinterpreted the intricate
arrangements of elongating Wbres as increases in Wbre
number (Paul and Rosenthal 2002). Indeed, studies
reporting an increase in the number of muscle Wbres used
avian or cat muscles (Kelley 1996). Both avian and cat
653
muscles have multiple endplate bands and Wbres that do
not insert into both tendons but terminate intrafascicu-
larly (Paul 2001). Thus, it remains to be determined
whether the radial growth of muscles with intrafascicu-
larly terminating Wbres in larger mammals arises from
new Wbre formation as assumed previously, or from
elongation of existing Wbres as recently proposed (Paul
and Rosenthal 2002). However, most human muscle fas-
cicles, despite their great length, consist of Wbres that
extend continuously from one tendon to the other with a
single nerve endplate band. Therefore, muscle hypertro-
phy in the adult human apparently can be accounted for
predominantly by hypertrophy of existing Wbres via
addition of newly constructed myoWbrils to the contrac-
tile apparatus. Accordingly, it has been suggested that
hyperplasia does not occur in humans following resis-
tance exercise (MacDougall et al. 1984; McCall et al.
1996). However, hyperplasia still remains a thinkable
mechanism of muscle enlargement. Thus, more conclu-
sive evidence might come from future investigations into
the plasticity of human muscle Wbre number. Fibre split-
ting or branching is also a characteristic feature of mus-
cle regeneration (Charge and Rudnicki 2004). Fibre
splitting is commonly observed in muscles from patients
suVering neuromuscular diseases, in hypertrophied mus-
cles, and in ageing mouse muscles, all of which are asso-
ciated with abnormal regenerative capacity (Bockhold
et al. 1998; Charge et al. 2002; SchiaVino et al. 1979). It
has been hypothesised that Wbre splitting occurs due to
the incomplete fusion of Wbres regenerating within the
same basal lamina (Blaivas and Carlson 1991; Bourke
and Ontell 1984).
Summarising, mechanical stress through high-inten-
sity resistance exercise (especially, but not exclusively
supramaximal eccentric exercise) inXicts myotrauma.
Upon myotrauma, quiescent satellite cells become acti-
vated: (1) through anabolic cytokines that are released
by the perturbed extracellular matrix; (2) by inWltrating
cells involved in the inXammatory response; (3) by the
damaged myoWbres; (4) in an autocrine manner by the
satellite cells themselves. Following activation, the satel-
lite cells proliferate, and ultimately fuse to existing mus-
cle Wbres or among themselves for tissue repair/
regeneration. Thus, besides myoW
bre hypertrophy due to
increased protein synthesis/decreased protein degrada-
tion (see “Cellular determinants of muscle hypertrophy
and atrophy”), satellite cell-based myoplasmic enlarge-
ment is a further mechanism in adult skeletal muscle
hypertrophy. It is consistent with the concept of the myo-
nuclear domain, where the satellite cells provide the
additional DNA for the establishment of additional
myonuclear domains during myoplasmic enlargement. It
follows that muscle damage is a further signiWcant mec-
hano-biological determinant of skeletal muscle size
adaptation. Thus, load magnitude (as a measure of extra-
cellular matrix and satellite cell perturbation) as well as
the number of lengthening contractions (as a measure or
eccentric damage) need to be speciWed in resistance exer-
Fig. 3 Hypothetical model of
skeletal muscle Wbre cytoplas-
mic enlargement. Schematically
depicted are satellite cells (red/
orange) lying beneath the basal
lamina and sarcolemma of mul-
tinucleated (dark blue) skeletal
muscle Wbres (cross and longitu-
dinal sections). According to the
concept of the myonuclear do-
main (see text for details), mus-
cle Wbre hypertrophy could
conceivably result from either
an increase in the size of existing
domains (dark blue shading)
(a!b and a!b⬘ for radial and
longitudinal hypertrophy,
respectively) or by an increase in
the number of domains by addi-
tion of new myonuclei (dark
blue) provided by the satellite
cells (red) (b!c / a!c and
b⬘!c⬘ / a⬘!c⬘ for radial and
longitudinal hypertrophy,
respectively)
654
cise reports (x
1
, x
2
, x
7
, Table 1). Additionally, successful
recovery (repair) from muscle injury depends on the bal-
ance between the degenerative and regenerative pro-
cesses. Importantly, degenerative and regenerative
processes are time-dependent. Thus, if resistance exercise
perturbations are delivered at very short time intervals,
the degenerative processes prevail. If the degenerative
processes prevail, muscle mass is lost. As a consequence,
studies in which subjects are resistance-trained over a
determinate period of time (x
6
, Table 1) should report
recovery times in between the exercise sessions (x
12
,
Table 1) and number of exercise interventions per week
(x
5
, Table 1), as a function of exercise-induced muscle
damage (exercise intensity). The importance of these
three factors (x
6
, x
12
, x
5
, Table 1) has been demonstrated
in studies, in which the duration of elevated protein turn-
over following resistance exercise sessions was investi-
gated (Chesley et al. 1992; MacDougall et al. 1995;
Phillips et al. 1997).
Molecular and cellular determinants of contractile
and metabolic tuning
Muscle Wbre has multiple, complex functional gene
groupings adapting independently to environmental
stimuli (Spangenburg and Booth 2003). The molecular
regulation of these functional gene groupings is Wbre
type-speciWc and results in the Wbre type’s phenotypical
characteristics. Such characteristics comprise, e.g. con-
tractile protein isoforms, mitochondrial volume, myoglo-
bin levels, capillary density, and oxidative enzyme
capacity. Each of these characteristics could be consid-
ered a functional gene domain within the respective Wbre
type (Spangenburg and Booth 2003). Not only can these
functional modules be regulated within diVerent myoW-
bres but also MyHC protein expression can be heteroge-
neous within a single Wbre (Pette and Staron 2000;
Talmadge et al. 1996), resulting in “hybrid” (Baldwin
and Haddad 2001) or “polymorphic” (Caiozzo et al.
2003) Wbres. It is believed that contractile activity follow-
ing neural activation induces changes in common regula-
tory factors within a subpopulation of genes (i.e. gene
“modules”) to modify the muscle Wbre phenotype
(Spangenburg and Booth 2003). More speciWcally, neural
activation of skeletal muscle results in the release of ace-
tylcholine from the neuromuscular junction and depolar-
isation of the plasma membrane, which activates force
production by a process known as excitation–contrac-
tion coupling. The frequency and duration of stimulation
determine the amplitude and duration of the Ca
2+
tran-
sients and, as a result, the level of force output by the
muscle. Thus, both the amplitude and duration of the
Ca
2+
transient in skeletal muscle are determined by the
motor unit (MU) Wring frequency. The increases in
amplitude, as well as the duration for which these ampli-
tudes are achieved, are thought to encode signals that
will be recognised by diVerent downstream Ca
2+
-depen-
dent pathways. The key signalling pathways downstream
of the elevation in intracellular Ca
2+
that translate this
signal into a transcriptional response include the Ca
2+
/
calmodulin(CaM)-dependent phosphatase calcineurin
(Cn), Ca
2+
/calmodulin-dependent kinase II (CaMKII),
Ca
2+
/calmodulin-dependent kinase IV (CaMKIV), and
Ca
2+
-dependent protein kinase C (PKC) (Chin 2005). In
turn, these Ca
2+
-dependent key signalling pathways will
determine the set of genes expressed, thus providing a
mechanism for tightly coupling the extent of muscle exci-
tation to regulation of transcription (i.e. excitation–tran-
scription coupling) (Chin 2005). Many Ca
2+
-sensitive
target genes have been identiWed in skeletal muscle.
Downstream Ca
2+
-sensitive target genes of varied
expression levels between Wbres include the nicotinic ace-
tylcholine receptor (nAChR), glucose transporter 4
(GLUT4), sarcoplasmic reticulum (SR) Ca
2+
ATPase
(SERCA1), MyHC isoforms, oxidative enzymes, as well
as genes that regulate mitochondrial biogenesis. Apart
from the transcriptional regulation, it has been suggested
that muscle Wbre contractile characteristics might also be
regulated by posttranslational modiWcation of contrac-
tile proteins (Canepari et al. 2005). In addition to the role
of Cn signalling in the determination of muscle Wbre type
characteristics, this phosphatase is known to play an
important role in muscle hypertrophy (Dunn et al. 1999;
Michel et al. 2004). Cn dephosphorylates the transcrip-
tion factor nuclear factor of activated T cells (NFAT),
enabling its nuclear translocation and DNA binding.
The Cn–NFAT pathway has been linked to Ca
2+
-
induced skeletal muscle hypertrophy, at least in cultured
skeletal muscle (Semsarian et al. 1999). With regard to
skeletal muscle hypertrophy in animal models, the role of
Cn remains controversial. Current thought suggests that
hyperactivation of Cn alone is not suYcient to induce
skeletal muscle hypertrophy but that the activation of
accessory parallel signalling pathways for growth is
required (Michel et al. 2004).
The size principle of motor recruitment—consequences
for resistance exercise
As mentioned above, amplitude and duration of Ca
2+
-
transients in skeletal muscle as a function of MU Wring
frequency are decoded at the molecular level, resulting in
expression changes of Wbre type-speciWc functional gene
modules. For mammals, it has been shown that for many
activities there is a graded level of muscle recruitment
that is driven by the diVerent thresholds of the motor
neurones: “the size principle of motor recruitment”
(Denny-Brown and Pennybacker 1938; Henneman et al.
1965, 1974). The size principle predicts that MU recruit-
ment is determined by force requirements. The majority
of units are, in fact, recruited voluntarily in the order of
increasing size (Monster and Chan 1977; Tanji and Kato
1973). Typically, small MUs are type I units, and unit
size increases with progression through the Wbre types:
I < IIA < IIX (according to the MyHC isoform classiW-
cation system in humans). Therefore, when low force is
655
required, only type I MUs will be active. Only when force
is high will recruitment demand involvement of the
larger MUs. It follows that slow muscle Wbres are acti-
vated for low-force contractions and fast muscle Wbres
are additionally activated to supply greater force
demands. Several researchers have shown that MU
recruitment is completed by »50% of maximum volun-
tary contraction (MVC) in small muscles [adductor polli-
cis (Kukulka and Clamann 1981), and Wrst dorsal
interosseus (De Luca et al. 1982a, b, 1996; Milner-Brown
et al. 1973)], and 70–80% of MVC in large muscles
[biceps (Kukulka and Clamann 1981), deltoid (De Luca
et al. 1982a, b), and tibialis anterior (De Luca et al. 1996;
Erim et al. 1996)]. The size principle applies when either
slow-ramp force is exerted or constant low forces are
compared with constant higher forces. The size principle
of orderly recruitment is also preserved during exercise
(Gollnick et al. 1974a, b; Vollestad and Blom 1985; Vol-
lestad et al. 1984, 1992), whether the comparison is of
sustained contractions at diVerent intensities, or at diVer-
ent times during exercise at the same submaximal force
sustained until exhaustion (Adam and De Luca 2003).
However, during some forms of voluntary or reXex
contraction, motor neurone size may not be the sole fac-
tor determining excitation threshold: (1) Specialisation
of the synaptic input among the motor neurones, and
joint position have been shown to aVect recruitment
order in some cases; (2) MU rotation strategy has been
demonstrated for sustained isometric contraction of
biceps brachii at 10 but not at 40% of maximum; (3) In
certain very rapid or sudden corrective movements—
such as accelerations or sudden changes in direction—
high-threshold units that do not participate in walking
or even in running might be selectively recruited, as
shown for the human short extensor muscle of the toes
(Grimby 1984). With respect to ballistic movements,
there is some controversy over the extent to which selec-
tive recruitment may occur (if at all) (Zehr and Sale
1994); (4) It has been suggested that selective recruitment
of large MUs occurs during lengthening contractions
(Nardone and Schieppati 1988; Nardone et al. 1989); (5)
In certain cases of altered motor tasks, recruitment order
might vary. Based on these results, it has been suggested
that diVerential recruitment simply represents the exis-
tence of distinct, task-related subpopulations of motor
units, rather than “violations” of the size principle
(Burke 2002; Cope and SokoloV 1999). Hence, when the
same motor task is undertaken in exactly the same way,
the order in which MUs are recruited remains Wxed. This
is of special importance, since it supports the notion that
recruitment order is maintained during muscular fatigue.
In particular, it has been shown that submaximal fatigu-
ing contractions in the vastus lateralis muscle of humans
lead to the monotonic decline in the recruitment thresh-
old of all MUs and the progressive recruitment of new
MUs, without change in the recruitment order. Thus, as
the force capacity of continuously active muscle Wbres
declines progressively, increased excitation is required to
keep the muscle output constant. The increased excita-
tion produces the recruitment of additional MUs. The
recruited MUs thus become active at a lower torque level
than their initial threshold, and the recruitment thresh-
old continues to decrease in subsequent contractions as
the force production of the active MUs continues to
decrease (Adam and De Luca 2003). Indeed, it could be
shown that the reduction in peak tetanic torque is line-
arly correlated with the decrease in the mean MU
recruitment threshold at corresponding endurance times
(beginning, middle, and end of fatiguing contractions)
(Adam and De Luca 2003). However, these data do not
prove a causal relationship between changes in muscle
force output and changes in MU recruitment. Nonethe-
less, it can reasonably be assumed that the drop in peak
tetanic torque that comes with muscular fatique corre-
sponds to an increase in the relative force requirement to
sustain the target torque level.
Based on these Wndings, we propose a theoretical
model of muscle fatigue and MU recruitment during
resistance exercise progression (Fig. 4). Provided that
exercise is performed to volitional muscular failure, the
three diVerent load magnitudes in Fig. 4a–c will lead to
similar, i.e. “complete” MU recruitment (Fig. 4d), and,
thus, to a similar stimulation of protein synthesis.
Indeed, preliminary studies aimed at delineating the
dose–response relationship between the intensity of exer-
cise and the rates of muscle protein synthesis have shown
that when the same total amount of ATP is turned over
and recruitment is complete, exercise at 60, 75, and 90%
of the 1RM results in exactly the same stimulation of
muscle protein synthesis (Bowtell et al. 2003). Addition-
ally, increases in tension above 65% cause no further
stimulation in muscle protein synthesis (Bowtell et al.
2003). However, the diVerent TUT until muscular failure
imply diVerent MU recruitment dynamics. As a conse-
quence, distinct metabolic loads are inXicted on the exer-
cising muscle in Fig. 4a–c. In Fig. 4a, progression
through the Wbre types I ! IIA ! IIX occurs fast (30 s).
In contrast, in Fig. 4c, progression through the Wbre
types occurs relatively slowly (180 s). Consequently, in
Fig. 4c the Wbres’ capability in providing ATP through
oxidative metabolism is more pronouncedly challenged
than in Fig. 4a. This is due to the fact that with low resis-
tive loads in % of the maximum voluntary torque
(MVT), the threshold for complete recruitment is
reached later. Thus, if a biceps exercise is assumed for the
examples in Fig. 4, only in Fig. 4a the recruitment is pre-
dicted to be complete at start. In Fig. 4b, c, complete
recruitment will be reached later. It follows directly, that
the two strategies of MU recruitment and MU Wring
rate-coding for the increase in force output will vary to
diVerent extents for Fig. 4a–c. Consequently, the distinct
pattern of MU recruitment and rate-coding in Fig. 4a–c
will have a diVerent impact on the previously described
excitation–transcription coupling (Chin 2005).
In conclusion, we deduce that the TUT (x
9
, Table 1),
volitional muscular failure (x
10
, Table 1), number of sets
(x
3
, Table 1), rest in-between sets (x
4
, Table 1), and rest
in-between repetitions (x
8
, Table 1) are further mechano-
656
biological determinants that aVect MU recruitment and
MU Wring rate-coding, and, thus, excitation–transcrip-
tion coupling. In addition, the number of exercise inter-
ventions per week (x
5
, Table 1) and the duration of the
experimental period (x
6
, Table 1) should be reported for
an estimation of the training’s stimulatory eVect on mus-
cle protein synthesis.
Molecular sensing of oxygen
Intramyocellular oxygen partial pressure has been sug-
gested to drop with exercise, leading to “local hypoxia”
(Gayeski et al. 1985). Local hypoxia, as determined by
measurement of oxygen saturation via assessment of myo-
globin desaturation, has been shown to occur within 20 s
of onset of exercise in human quadriceps muscle (Rich-
ardson et al. 1995). Additionally, oxygen saturation is
reduced to a plateau with the onset of exercise (Richard-
son et al. 2001). Thus, it has been hypothesised that local
hypoxic conditions may prevail in muscle even during low
intensity exercise in normoxia (Hoppeler et al. 2003).
The partial pressure of cellular oxygen is sensed by a
family of prolyl hydroxylases (Wenger et al. 2005). This
enzyme family contains three members: prolyl-4-hydrox-
ylase domain 1 (PHD1), PHD2, and PHD3, also known
as hypoxia-inducible factor (HIF) prolyl hydroxylase 3
Fig. 4 Hypothetical model of muscle fatigue and its consequences
for motor unit recruitment and, thus, for the metabolic load imposed
on a skeletal muscle. In this simplistic model (e.g. biceps brachii per-
forming 1 set of resistance exercise to volitional muscular failure), it
is assumed that the drop in % of the maximum voluntary torque
(MVT) in-between the repetitions (i.e. the “fatigue inroad”) occurs
with constant percentage. The magnitude of fatigue inroad per repe-
tition is assumed to be 6, 3.5, and 2.5% for high (magenta bars), inter-
mediate (cyan bars), and low (yellow bars) resistive loads,
respectively. The primary ordinates in a–c indicate the load magni-
tude expressed in % of the MVT achieved at a determinate joint an-
gle. The abscissae in a–d indicate the total time (s) under tension until
muscular failure (TUTF) or the corresponding number of repetitions
when 10 s movement time per repetition is assumed. The secondary
ordinates in a–c indicate the resistive load (i.e. the “training load”) in
% of MVT at t = t
0
. The ordinate in d indicates the resistive load in
% of MVT through exercise progression, which corresponds to the
relative resistive MVT. A high (magenta bars), intermediate (cyan
bars), and low (yellow bars) resistive load is assumed in a–c, respec-
tively. These high, intermediate, and low resistive loads correspond
to high, intermediate, and low % of MVT. Moreover, these resistive
loads (“training loads”) remain unchanged during the same exercise
set. However, the theoretical MVT (black bars) declines with exercise
progression due to muscular fatigue, with a concurrent increase in
motor unit (MU) recruitment and MU Wring rate (see text for de-
tails). The time point of muscular failure corresponds to the point at
which the theoretical MVT is below the MVT required to overcome
the resistive load. Muscular failure occurs after 30 s (3 repetitions),
90 s (9 repetitions), and 180 s (18 repetitions) in examples a–c, respec-
tively. In d, the hypothetical increase in relative resistive load (%
MVT) for high (magenta), intermediate (cyan), and low (yellow)
resistive loads [% MVT (t = t
0
)] is plotted against the TUTF. The
relative load [% MVT (t = t
0
)] as exercise starts and the steepness
with which it increases through exercise progression until voluntary
failure, as a function of the muscle’s Wbre type distribution, deter-
mines MU recruitment. The grey shaded area corresponds to the pre-
dicted resistive load in % of MVT at which MU recruitment for
biceps brachii muscle is completed (see text for details)
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
Resistive load in % MVT (t = t
0
)
Resistive load in % MVT (t = t
0
)
Resistive load in % MVT (t = t
0
)
% MVT
% MVT
Resistive load in % MVT
TUTF (s) (# of 10s-repetitions)
TUTF (s) (# of 10s-repetitions)
TUTF (s) (# of 10s-repetitions)
TUTF (s) (# of 10s-repetitions)
10 (1)
20 (2)
30 (3)
10 (1)
20 (2)
30 (3)
40 (4)
50 (5)
60 (6)
70 (7)
80 (8)
90 (9)
10 (1)
20 (2)
30 (3)
40 (4)
50 (5)
60 (6)
70 (7)
80 (8)
90 (9)
100 (10)
110 (11)
120 (12)
130 (13)
140 (14)
150 (15)
160 (16)
170 (17)
180 (18)
10 (1)
20 (2)
30 (3)
40 (4)
50 (5)
60 (6)
70 (7)
80 (8)
90 (9)
100 (10)
110 (11)
120 (12)
130 (13)
140 (14)
150 (15)
160 (16)
170 (17)
180 (18)
ab
cd
% MVT
657
(HPH3), HPH2, and HPH1, respectively. The prolyl
hydroxylases covalently modify HIF subunits. HIF is a
heterodimeric transcription factor consisting of one of
three diVerent oxygen-sensitive HIF subunits and a
common constitutive HIF subunit. Under normoxic
conditions, HIF is hydroxylated. HIF hydroxylation
promotes von Hippel–Lindau (VHL) tumour suppressor
protein binding to HIF. Upon binding of VHL, HIF is
targeted for proteasomal destruction. Under hypoxic
conditions, however, PHD activity (and thus HIF
hydroxylation) decreases. Thus, under hypoxic condi-
tions, the high turnover rate of HIF subunits enables
the very rapid accumulation of HIF. Following a fur-
ther decrease in oxygen availability, the asparagine
hydroxylase function of another enzyme, the factor
inhibiting HIF (FIH), also becomes impaired, resulting
in a decrease in HIF C-terminal hydroxylation. This
decrease in C-terminal HIF hydroxylation enables the
increased recruitment of the p300 and CREB-binding
protein (p300/CBP) transcriptional coactivators, leading
to the enhanced transcriptional activation of at least 70
diVerent HIF eVector genes (Wenger et al. 2005).
HIF eVector genes regulate, e.g., oxygen supply, cellu-
lar metabolism, cell growth, and apoptosis (Wenger et al.
2005). Indeed, it has recently been shown that HIF1
protein abundance increases in response to the acute
exercise-induced increase in oxygen demand in human
tissue (Ameln et al. 2005). Concurrently, no changes in
HIF1 mRNA abundance were detected in response to
exercise. Thus, it was suggested that the observed
increased HIF1 protein abundance mainly depends on
posttranscriptional mechanisms. In parallel with the
exercise-induced stabilisation of HIF1 protein, nuclear
translocation of the protein was observed, together with
an induced expression of the HIF regulated target genes.
In particular, vascular endothelial factor (VEGF) and
erythropoietin (EPO) mRNA abundance was increased
with exercise (Ameln et al. 2005).
The role of HIF1 in regulating skeletal muscle func-
tion has recently also been investigated with HIF1
knockout mice (HIF1 KOs) (Mason et al. 2004). It was
found that a signiWcant exercise-induced increase in
mRNA abundance of VEGF, GLUT4, muscle-speciWc
phosphofructokinase (PFK-M), phosphoglycerate kinase
(PGK), and lactate dehydrogenase-A (LDH-A) is missing
in HIF1 KOs compared to wild-type (WT) mice. Also,
changes in enzymatic activity in a number of key glyco-
lytic enzymes are aVected by deletion of HIF1. In partic-
ular, the activity of one of the key rate-limiting enzymes,
PFK, is signiWcantly lower following exercise in HIF1
KOs compared to WT mice. In HIF1 KOs, overall, a
metabolic shift away from glycolysis towards oxidation
was observed. This metabolic shift away from glycolysis
towards oxidation increases swimming and uphill run-
ning exercise times in the HIF1 KOs. Conversely,
repeated bouts of downhill running (eccentric exercise)
results in greatly reduced exercise times and increased
muscle damage in HIF1 KOs relative to WT mice. The
authors hypothesised that the reduced exercise times with
eccentric exercise is due to the impaired glycolytic capac-
ity in HIF1 KOs (Mason et al. 2004). This assumption
was based on the previous Wndings that primarily fast-
twitch glycolytic Wbres are activated for eccentric contrac-
tion (Nardone and Schieppati 1988; Nardone et al. 1989).
Further evidence for the molecular regulation of skele-
tal muscle metabolic properties through regulation of
Wbre type functional modules has recently come from the
engineering of a mouse capable of continuous running of
up to twice the distance of a WT littermate (Wang et al.
2004). These authors uncovered peroxisome proliferator-
activated receptor (PPAR) as the Wrst transcription fac-
tor able to drive a metabolic Wbre reprogramming follow-
ing the targeted expression of an activated form of
PPAR. PPAR produces profound and coordinated
increases in oxidation enzymes, mitochondrial biogenesis,
and production of specialised type I Wbre contractile pro-
teins—the three hallmarks for muscle Wbre type switch-
ing. The muscle phenotypes described in that study are
remarkably similar to those of transgenic mice expressing
either Cn, CaM kinase, or peroxisome proliferator-acti-
vated receptor-gamma coactivator 1 (PGC-1) (Lin
et al. 2002; Naya et al. 2000; Wu et al. 2002). Thus, it was
suggested that PPAR could be one of the hypothetical
downstream transcription factors of these pathways
(Wang et al. 2004). However, according to ligand and
gain-of-function transgenic studies, PPAR needs to be
activated in order to direct the muscle Wbre switch.
Indeed, in a recent report, simple overexpression of WT
PPAR in muscle was found not to be suYcient to pro-
mote a Wbre switch or obesity resistance, although certain
oxidation enzymes are increased (Luquet et al. 2003). This
supports the notion that the activating signal or ligand,
but not the receptor, is limiting (Wang et al. 2004). Thus,
PPAR activation, rather than merely an increase of
PPAR levels, is an essential element for Wbre switching
and its associated functional manifestations. Two models
have been proposed for the exercise-induced activation of
endogenous PPAR (Wang et al. 2004). First, it is possi-
ble that exercise generates or increases endogenous
ligands for PPAR as tissues are undergoing substantial
increases in fatty-acid internalisation and oxidation.
Fatty acids and their metabolites can activate PPAR. A
second model is that exercise may induce the expression
of PGC-1 (Goto et al. 2000) and thereby activate
PPAR. This is consistent with previous work in which it
was shown that PGC-1 physically associates with
PPAR in muscle tissue and can powerfully activate it
even in the absence of ligands (Wang et al. 2003). In line
with these Wndings in rodent muscles, two recent studies
show that one-legged knee extensor exercise of diVerent
duration and blood supply conditions induce transcrip-
tional activation of the PGC-1 gene in human skeletal
muscle (Norrbom et al. 2004; Pilegaard et al. 2003).
Impairment of blood supply following low-intensity exer-
cise with superimposed vascular occlusion has also been
shown to stimulate hypertrophy to a greater degree than
exercise without occlusion (Abe et al. 2005; Moore et al.
2004; Takarada et al. 2002, 2004).
658
In summary, it can be derived that decreased oxygen
supply to skeletal muscle during resistance exercise
aVects myocellular oxygen homeostasis. Oxygen supply
to skeletal muscle is inXuenced by the magnitude of
active and/or passive tension that is generated during
exercise as well as by the modality of exercise (Vedsted
et al. 2006). Magnitude of active and/or passive tension
dictates to which extent blood Xow is reduced. Modality
of exercise, i.e. constant versus intermittent tension deliv-
ery, is a measure of how long and how many times blood
Xow is reduced. For example, during “eccentric only”
resistance exercise (such as “negative chins” or “negative
dips”), only lengthening contractions are performed.
Negative chins/dips are performed by climbing into the
top position using the legs and by lowering the body
back down by the lengthening contractions of the respec-
tive target muscles. Consequently, while climbing into
the top position, target muscle blood Xow is less chal-
lenged than during the lowering phase. Thus, we con-
clude that load magnitude (x
1
, Table 1), TUT (x
9
,
Table 1), contraction mode and fractional distribution
per repetition (x
7
, Table 1), rest in-between repetitions
(x
8
, Table 1), as well as ROM (x
11
, Table 1), are signiW-
cant mechano-biological determinants of myocellular
oxygen homeostasis. Therefore, they need to be speciWed
in resistance exercise protocols. It must also be empha-
sised that the total TUT does not necessarily just corre-
spond to the number of repetitions times the time
requirement for one repetition. If the exercise is per-
formed to volitional muscular failure, the TUT corre-
sponds to the TUT until failure (TUTF). TUTF includes
an isometric contraction of maximal time duration at the
end of exercise. Thus, TUTF may exceed the product of
the number of repetitions times the time requirement for
one repetition.
Recommendations for optimal exercise stimulus design
and description
Skeletal muscle is a biological tissue. As such, it adapts to
mechano-biological conditions that are present or miss-
ing. As described in this paper, these mechano-biological
conditions lead to the induction of molecular and cellu-
lar determinants for the regulation of skeletal muscle
girth, length, and Wbre type. Thus, we propose to view
(resistance) “exercise” as physiological tissue condition-
ing, i.e., the targeted delivery of muscular stimuli of
quantitative and/or qualitative eVect on the muscular
phenotype. Whether and to which extent an adaptation
occurs is subordinate to the “response matrix” of the
respective subject (Fig. 1). Targeted delivery of adapta-
tional stimuli precludes an accurate mechano-biological
description of the condition. Unfortunately, most of the
past and present resistance exercise prescriptions (Kra-
emer and Ratamess 2004) still use ambiguous stimulus
descriptors. This shortcoming makes it a priori virtually
impossible to identify which stimuli lead to what kind of
adaptation. Consequently, no exercise prescriptions with
speciWc eVect, e.g. for the prevention and/or treatment of
sarcopenia and metabolic diseases, exist. In order to
allow for a dissection of the relative contributions of
exercise stimuli and response matrix to muscular adapta-
tion, we have identiWed and described a basic set of resis-
tance exercise-related muscular conditions and termed
them “mechano-biological determinants of muscular
adaptation” (Table 1). While most of these determinants
are scientiWcally tested, some are hypothetical (e.g. rest
in-between repetitions). Understanding the relative con-
tribution of theses determinants in modulating the skele-
tal muscle phenotype should provide the basis for the
design and prescription of training stimuli with speciWc
quantitative and/or qualitative eVect. We are aware of
the fact that the use of 13 descriptors might raise some
concerns with respect to practicability. However, we con-
sider these determinants mandatory information for sci-
entiWc experiments that aim at identifying causal
connections between stimulus and response. Conse-
quently, we strongly recommend to standardise the
design and description of all future resistance exercise
investigations by using the herein proposed basic set of
13 mechano-biological determinants (classical and new
ones). Finally, although some of the newly proposed
descriptors (e.g. TUT) are already employed by some
exercise specialists, the identiWcation of graded quantita-
tive and qualitative eVects of the most important descrip-
tors should improve the eVectiveness of future exercise
recommendations.
References
Abe T, Kearns CF, Sato Y (2006) Muscle size and strength are in-
creased following walk training with restricted venous blood
Xow from the leg muscle, Kaatsu-walk training. J Appl Physiol
100:1460–1466
Adam A, De Luca CJ (2003) Recruitment order of motor units in
human vastus lateralis muscle is maintained during fatiguing
contractions. J Neurophysiol 90:2919–2927
Adams GR, Caiozzo VJ, Haddad F, Baldwin KM (2002) Cellular
and molecular responses to increased skeletal muscle loading af-
ter irradiation. Am J Physiol Cell Physiol 283:C1182–C1195
Aihara Y, Kurabayashi M, Saito Y, Ohyama Y, Tanaka T, Takeda
S, Tomaru K, Sekiguchi K, Arai M, Nakamura T, Nagai R
(2000) Cardiac ankyrin repeat protein is a novel marker of car-
diac hypertrophy: role of M-CAT element within the promoter.
Hypertension 36:48–53
Allen RE, Sheehan SM, Taylor RG, Kendall TL, Rice GM (1995)
Hepatocyte growth factor activates quiescent skeletal muscle
satellite cells in vitro. J Cell Physiol 165:307–312
Allen DL, Roy RR, Edgerton VR (1999) Myonuclear domains in
muscle adaptation and disease. Muscle Nerve 22:1350–1360
Allen DG, Whitehead NP, Yeung EW (2005) Mechanisms of
stretch-induced muscle damage in normal and dystrophic mus-
cle: role of ionic changes. J Physiol (Lond) 567:723–735
Ameln H, Gustafsson T, Sundberg CJ, Okamoto K, Jansson E, Poel-
linger L, Makino Y (2005) Physiological activation of hypoxia
inducible factor-1 in human skeletal muscle. Faseb J 19:1009–1011
Anderson JE (2000) A role for nitric oxide in muscle repair: nitric
oxide-mediated activation of muscle satellite cells. Mol Biol Cell
11:1859–1874
659
Anderson J, Pilipowicz O (2002) Activation of muscle satellite cells
in single-Wber cultures. Nitric Oxide 7:36–41
Armstrong RB, Warren GL, Warren JA (1991) Mechanisms of exer-
cise-induced muscle Wbre injury. Sports Med 12:184–207
Aronson D, Boppart MD, Dufresne SD, Fielding RA, Goodyear LJ
(1998) Exercise stimulates c-Jun NH
2
kinase activity and c-Jun
transcriptional activity in human skeletal muscle. Biochem Bio-
phys Res Commun 251:106–110
Baldwin KM, Haddad F (2001) EVects of diVerent activity and inac-
tivity paradigms on myosin heavy chain gene expression in stri-
ated muscle. J Appl Physiol 90:345–357
Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Good-
man A, McLaVerty CL Jr, Urban RJ (2001) Mechanical load in-
creases muscle IGF-I and androgen receptor mRNA
concentrations in humans. Am J Physiol Endocrinol Metab
280:E383–E390
Baracos VE (2001) Management of muscle wasting in cancer-associ-
ated cachexia: understanding gained from experimental studies.
Cancer 92:1669–1677
Barash IA, Mathew L, Ryan AF, Chen J, Lieber RL (2004) Rapid
muscle-speciWc gene expression changes after a single bout of
eccentric contractions in the mouse. Am J Physiol Cell Physiol
286:C355–C364
Barash IA, Mathew L, Lahey M, Greaser ML, Lieber RL (2005)
Muscle LIM protein plays both structural and functional roles in
skeletal muscle. Am J Physiol Cell Physiol 289:C1312–C1320
Baumeister A, Arber S, Caroni P (1997) Accumulation of muscle
ankyrin repeat protein transcript reveals local activation of pri-
mary myotube endcompartments during muscle morphogenesis.
J Cell Biol 139:1231–1242
Bey L, Akunuri N, Zhao P, HoVman EP, Hamilton DG, Hamilton
MT (2003) Patterns of global gene expression in rat skeletal mus-
cle during unloading and low-intensity ambulatory activity.
Physiol Genomics 13:157–167
BischoV R (1997) Chemotaxis of skeletal muscle satellite cells. Dev
Dyn 208:505–515
Blaivas M, Carlson BM (1991) Muscle Wber branching—diVerence
between grafts in old and young rats. Mech Ageing Dev 60:43–53
Bockhold KJ, Rosenblatt JD, Partridge TA (1998) Aging normal
and dystrophic mouse muscle: analysis of myogenicity in cul-
tures of living single Wbers. Muscle Nerve 21:173–183
Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA,
Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ,
Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD,
Glass DJ (2001a) IdentiWcation of ubiquitin ligases required for
skeletal muscle atrophy. Science 294:1704–1708
Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein
R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yanc-
opoulos GD (2001b) Akt/mTOR pathway is a crucial regulator
of skeletal muscle hypertrophy and can prevent muscle atrophy
in vivo. Nat Cell Biol 3:1014–1019
Booth FW, Kelso JR (1973) Production of rat muscle atrophy by
cast Wxation. J Appl Physiol 34:404–406
Boppart MD, Aronson D, Gibson L, RoubenoV R, Abad LW, Bean
J, Goodyear LJ, Fielding RA (1999) Eccentric exercise markedly
increases c-Jun NH
2
-terminal kinase activity in human skeletal
muscle. J Appl Physiol 87:1668–1673
Bourke DL, Ontell M (1984) Branched myoWbers in long-term
whole muscle transplants: a quantitative study. Anat Rec
209:281–288
Bowtell J, Park DM, Smith K, Cuthbertson DJR, Waddell T, Rennie
MJ (2003) Stimulation of human quadriceps protein synthesis
after strenous exercise: no eVects of varying intensity between 60
and 90% of one repetition maximum (1RM). J Physiol (Lond)
547P:P16
Brockett CL, Morgan DL, Proske U (2001) Human hamstring mus-
cles adapt to eccentric exercise by changing optimum length.
Med Sci Sports Exerc 33:783–790
Brooks GA (2005) Governor recalled! Now what? J Physiol (Lond)
568:355
Burke RE (2002) Some unresolved issues in motor unit research.
Adv Exp Med Biol 508:171–178
ButterWeld TA, Leonard TR, Herzog W (2005) DiVerential serial
sarcomere number adaptations in knee extensor muscles of rats
is contraction type dependent. J Appl Physiol 99:1352–1358
Caiozzo VJ, Baker MJ, Huang K, Chou H, Wu YZ, Baldwin KM
(2003) Single-Wber myosin heavy chain polymorphism: how
many patterns and what proportions? Am J Physiol Regul Integr
Comp Physiol 285:R570–R580
Canepari M, Rossi R, Pellegrino MA, Orrell RW, Cobbold M, Har-
ridge S, Bottinelli R (2005) EVects of resistance training on myo-
sin function studied by the in vitro motility assay in young and
older men. J Appl Physiol 98:2390–2395
Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC,
Bang ML, Trombitas K, Granzier H, Gregorio CC, Sorimachi
H, Labeit S (2001) IdentiWcation of muscle speciWc ring Wnger
proteins as potential regulators of the titin kinase domain. J Mol
Biol 306:717–726
Chakravarthy MV, Abraha TW, Schwartz RJ, Fiorotto ML, Booth
FW (2000a) Insulin-like growth factor-I extends in vitro replica-
tive life span of skeletal muscle satellite cells by enhancing G1/S
cell cycle progression via the activation of phosphatidylinositol
3’-kinase/Akt signaling pathway. J Biol Chem 275:35942–35952
Chakravarthy MV, Davis BS, Booth FW (2000b) IGF-I restores sat-
ellite cell proliferative potential in immobilized old skeletal mus-
cle. J Appl Physiol 89:1365–1379
Charge SB, Rudnicki MA (2004) Cellular and molecular regulation
of muscle regeneration. Physiol Rev 84:209–238
Charge SB, Brack AS, Hughes SM (2002) Aging-related satellite cell
diVerentiation defect occurs prematurely after Ski-induced mus-
cle hypertrophy. Am J Physiol Cell Physiol 283:C1228–C1241
Cheek DB (1985) The control of cell mass and replication. The DNA
unit - a personal 20-year study. Early Hum Dev 12:211–239
Chen YW, Nader GA, Baar KR, Fedele MJ, HoVman EP, Esser KA
(2002) Response of rat muscle to acute resistance exercise deWned
by transcriptional and translational proWling. J Physiol (Lond)
545:27–41
Chesley A, MacDougall JD, Tarnopolsky MA, Atkinson SA, Smith
K (1992) Changes in human muscle protein synthesis after resis-
tance exercise. J Appl Physiol 73:1383–1388
Chin ER (2005) Role of Ca
2+
/calmodulin-dependent kinases in skel-
etal muscle plasticity. J Appl Physiol 99:414–423
Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery
C, Schwartz RJ (1995) Myogenic vector expression of insulin-
like growth factor I stimulates muscle cell diVerentiation and
myoWber hypertrophy in transgenic mice. J Biol Chem
270:12109–12116
Cope TC, SokoloV AJ (1999) Orderly recruitment among motoneu-
rons supplying diVerent muscles. J Physiol (Paris) 93:81–85
Cros N, Tkatchenko AV, Pisani DF, Leclerc L, Leger JJ, Marini JF,
Dechesne CA (2001) Analysis of altered gene expression in rat
soleus muscle atrophied by disuse. J Cell Biochem 83:508–519
Darr KC, Schultz E (1987) Exercise-induced satellite cell activation
in growing and mature skeletal muscle. J Appl Physiol 63:1816–
1821
De Luca CJ, LeFever RS, McCue MP, Xenakis AP (1982a) Behav-
iour of human motor units in diVerent muscles during linearly
varying contractions. J Physiol (Lond) 329:113–128
De Luca CJ, LeFever RS, McCue MP, Xenakis AP (1982b) Control
scheme governing concurrently active human motor units during
voluntary contractions. J Physiol (Lond) 329:129–142
De Luca CJ, Foley PJ, Erim Z (1996) Motor unit control properties
in constant-force isometric contractions. J Neurophysiol
76:1503–1516
DeVol DL, Rotwein P, Sadow JL, Novakofski J, Bechtel PJ (1990)
Activation of insulin-like growth factor gene expression during
work-induced skeletal muscle growth. Am J Physiol 259:E89–
E95
Decary S, Mouly V, Hamida CB, Sautet A, Barbet JP, Butler-
Browne GS (1997) Replicative potential and telomere length in
human skeletal muscle: implications for satellite cell-mediated
gene therapy. Hum Gene Ther 8:1429–1438
Denny-Brown D, Pennybacker JB (1938) Fibrillation and fascicula-
tion in voluntary muscle. Brain 61:311–334
660
Dhawan J, Rando TA (2005) Stem cells in postnatal myogenesis:
molecular mechanisms of satellite cell quiescence, activation and
replenishment. Trends Cell Biol 15:666–673
Dix DJ, Eisenberg BR (1990) Myosin mRNA accumulation and
myoWbrillogenesis at the myotendinous junction of stretched
muscle Wbers. J Cell Biol 111:1885–1894
Dunn SE, Burns JL, Michel RN (1999) Calcineurin is required for
skeletal muscle hypertrophy. J Biol Chem 274:21908–21912
Dupont Salter AC, Richmond FJ, Loeb GE (2003) EVects of muscle
immobilization at diVerent lengths on tetrodotoxin-induced dis-
use atrophy. IEEE Trans Neural Syst Rehabil Eng 11:209–217
Edgerton VR, Roy RR (1991) Regulation of skeletal muscle Wber
size, shape and function. J Biomech 24(Suppl 1):123–133
Erim Z, De Luca CJ, Mineo K, Aoki T (1996) Rank-ordered regula-
tion of motor units. Muscle Nerve 19:563–573
Farthing JP, Chilibeck PD (2003) The eVects of eccentric and con-
centric training at diVerent velocities on muscle hypertrophy.
Eur J Appl Physiol 89:578–586
Faulkner JA, Brooks SV, Opiteck JA (1993) Injury to skeletal mus-
cle Wbers during contractions: conditions of occurrence and pre-
vention. Phys Ther 73:911–921
Ferrell RE, Conte V, Lawrence EC, Roth SM, Hagberg JM, Hurley
BF (1999) Frequent sequence variation in the human myostatin
(GDF8) gene as a marker for analysis of muscle-related pheno-
types. Genomics 62:203–207
Fielding RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, Can-
non JG (1993) Acute phase response in exercise. III. Neutrophil
and IL-1 accumulation in skeletal muscle. Am J Physiol
265:R166–R172
Gayeski TE, Connett RJ, Honig CR (1985) Oxygen transport in
rest-work transition illustrates new functions for myoglobin. Am
J Physiol 248:H914–H921
Gibala MJ, MacDougall JD, Tarnopolsky MA, Stauber WT, Elor-
riaga A (1995) Changes in human skeletal muscle ultrastructure
and force production after acute resistance exercise. J Appl Phys-
iol 78:702–708
Glass DJ (2003a) Molecular mechanisms modulating muscle mass.
Trends Mol Med 9:344–350
Glass DJ (2003b) Signalling pathways that mediate skeletal muscle
hypertrophy and atrophy. Nat Cell Biol 5:87–90
Glass DJ (2005) Skeletal muscle hypertrophy and atrophy signaling
pathways. Int J Biochem Cell Biol 37:1974–1984
Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome
proteolytic pathway: destruction for the sake of construction.
Physiol Rev 82:373–428
Goldspink G (1985) Malleability of the motor system: a compara-
tive approach. J Exp Biol 115:375–391
Goldspink G (2005) Mechanical signals, IGF-I gene splicing, and
muscle adaptation. Physiology 20:232–238
Goldspink G, Scutt A, Martindale J, Jaenicke T, Turay L, Gerlach
GF (1991) Stretch and force generation induce rapid hypertro-
phy and myosin isoform gene switching in adult skeletal muscle.
Biochem Soc Trans 19:368–373
Goldspink G, Scutt A, Loughna PT, Wells DJ, Jaenicke T, Gerlach
GF (1992) Gene expression in skeletal muscle in response to
stretch and force generation. Am J Physiol 262:R356–R363
Gollnick PD, Karlsson J, Piehl K, Saltin B (1974a) Selective glyco-
gen depletion in skeletal muscle Wbres of man following sus-
tained contractions. J Physiol (Lond) 241:59–67
Gollnick PD, Piehl K, Saltin B (1974b) Selective glycogen depletion
pattern in human muscle Wbres after exercise of varying intensity
and at varying pedalling rates. J Physiol (Lond) 241:45–57
Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001)
Atrogin-1, a muscle-speciWc F-box protein highly expressed
during muscle atrophy. Proc Natl Acad Sci USA 98:14440–
14445
Gordon ES, Gordish Dressman HA, HoVman EP (2005) The genet-
ics of muscle atrophy and growth: the impact and implications of
polymorphisms in animals and humans. Int J Biochem Cell Biol
37:2064–2074
Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I, Shim-
okawa T (2000) cDNA cloning and mRNA analysis of PGC-1 in
epitrochlearis muscle in swimming-exercised rats. Biochem Bio-
phys Res Commun 274:350–354
GriYn GE, Williams PE, Goldspink G (1971) Region of longitudi-
nal growth in striated muscle Wbres. Nat New Biol 232:28–29
Grimby L (1984) Firing properties of single human motor units dur-
ing locomotion. J Physiol (Lond) 346:195–202
Haddad F, Adams GR (2002) Selected contribution: acute cellular
and molecular responses to resistance exercise. J Appl Physiol
93:394–403
Hall ZW, Ralston E (1989) Nuclear domains in muscle cells. Cell
59:771–772
Hameed M, Orrell RW, Cobbold M, Goldspink G, Harridge SD
(2003) Expression of IGF-I splice variants in young and old hu-
man skeletal muscle after high resistance exercise. J Physiol
(Lond) 547:247–254
Hanzlikova V, Mackova EV, Hnik P (1975) Satellite cells of the rat
soleus muscle in the process of compensatory hypertrophy com-
bined with denervation. Cell Tissue Res 160:411–421
Henneman E, Somjen G, Carpenter DO (1965) Functional signiW-
cance of cell size in spinal motoneurons. J Neurophysiol 28:560–
580
Henneman E, Clamann HP, Gillies JD, Skinner RD (1974) Rank or-
der of motoneurons within a pool: law of combination. J Neuro-
physiol 37:1338–1349
Hentzen ER, Lahey M, Peters D, Mathew L, Barash IA, Friden J,
Lieber RL (2006) Stress-dependent and -independent expression
of the myogenic regulatory factors and the MARP genes after
eccentric contractions in rats. J Physiol (Lond) 570:157–167
Hill M, Goldspink G (2003) Expression and splicing of the insulin-
like growth factor gene in rodent muscle is associated with mus-
cle satellite (stem) cell activation following local tissue damage. J
Physiol (Lond) 549:409–418
Hill M, Wernig A, Goldspink G (2003) Muscle satellite (stem) cell
activation during local tissue injury and repair. J Anat 203:89–99
Hoppeler H, Vogt M, Weibel ER, Fluck M (2003) Response of skel-
etal muscle mitochondria to hypoxia. Exp Physiol 88:109–119
Hoyt DF, Wickler SJ, Biewener AA, Cogger EA, De La Paz KL
(2005) In vivo muscle function vs speed. I. Muscle strain in rela-
tion to length change of the muscle-tendon unit. J Exp Biol
208:1175–1190
Hubal MJ, Gordish-Dressman H, Thompson PD, Price TB, HoV-
man EP, Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello
LS, Visich PS, Zoeller RF, Seip RL, Clarkson PM (2005) Vari-
ability in muscle size and strength gain after unilateral resistance
training. Med Sci Sports Exerc 37:964–972
Ikeda K, Emoto N, Matsuo M, Yokoyama M (2003) Molecular
identiWcation and characterization of a novel nuclear protein
whose expression is up-regulated in insulin-resistant animals. J
Biol Chem 278:3514–3520
Ingber DE (2003a) Tensegrity I. Cell structure and hierarchical sys-
tems biology. J Cell Sci 116:1157–1173
Ingber DE (2003b) Tensegrity II. How structural networks inXuence
cellular information processing networks. J Cell Sci 116:1397–
1408
Isfort RJ, Hinkle RT, Jones MB, Wang F, Greis KD, Sun Y, Keough
TW, Anderson NL, Sheldon RJ (2000) Proteomic analysis of the
atrophying rat soleus muscle following denervation. Electropho-
resis 21:2228–2234
Isfort RJ, Wang F, Greis KD, Sun Y, Keough TW, Bodine SC,
Anderson NL (2002a) Proteomic analysis of rat soleus and tibi-
alis anterior muscle following immobilization. J Chromatogr B
Analyt Technol Biomed Life Sci 769:323–332
Isfort RJ, Wang F, Greis KD, Sun Y, Keough TW, Farrar RP, Bo-
dine SC, Anderson NL (2002b) Proteomic analysis of rat soleus
muscle undergoing hindlimb suspension-induced atrophy and
reweighting hypertrophy. Proteomics 2:543–550
Ivey FM, Roth SM, Ferrell RE, Tracy BL, Lemmer JT, Hurlbut
DE, Martel GF, Siegel EL, Fozard JL, JeVrey Metter E, Fleg
JL, Hurley BF (2000) EVects of age, gender, and myostatin
genotype on the hypertrophic response to heavy resistance
strength training. J Gerontol A Biol Sci Med Sci 55:M641–
M648
661
Jackman RW, Kandarian SC (2004) The molecular basis of skeletal
muscle atrophy. Am J Physiol Cell Physiol 287:C834–843
Jagoe RT, Lecker SH, Gomes M, Goldberg AL (2002) Patterns of
gene expression in atrophying skeletal muscles: response to food
deprivation. Faseb J 16:1697–1712
Kadi F, Eriksson A, Holmner S, Butler-Browne GS, Thornell LE
(1999a) Cellular adaptation of the trapezius muscle in strength-
trained athletes. Histochem Cell Biol 111:189–195
Kadi F, Eriksson A, Holmner S, Thornell LE (1999b) EVects of ana-
bolic steroids on the muscle cells of strength-trained athletes.
Med Sci Sports Exerc 31:1528–1534
Kadi F, Schjerling P, Andersen LL, ChariW N, Madsen JL, Christen-
sen LR, Andersen JL (2004) The eVects of heavy resistance train-
ing and detraining on satellite cells in human skeletal muscles. J
Physiol (Lond) 558:1005–1012
Kandarian SC, Jackman RW (2006) Intracellular signaling during
skeletal muscle atrophy. Muscle Nerve 33:155–165
Kelley G (1996) Mechanical overload and skeletal muscle Wber
hyperplasia: a meta-analysis. J Appl Physiol 81:1584–1588
Kemp TJ, Sadusky TJ, Saltisi F, Carey N, Moss J, Yang SY, Sassoon
DA, Goldspink G, Coulton GR (2000) IdentiWcation of Ankrd2,
a novel skeletal muscle gene coding for a stretch-responsive
ankyrin-repeat protein. Genomics 66:229–241
Knoll R, Hoshijima M, HoVman HM, Person V, Lorenzen-Schmidt
I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W,
McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch
AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss
HP, Chien KR (2002) The cardiac mechanical stretch sensor
machinery involves a Z disc complex that is defective in a subset
of human dilated cardiomyopathy. Cell 111:943–955
Kraemer WJ, Ratamess NA (2004) Fundamentals of resistance
training: progression and exercise prescription. Med Sci Sports
Exerc 36:674–688
Kukulka CG, Clamann HP (1981) Comparison of the recruitment
and discharge properties of motor units in human brachial bi-
ceps and adductor pollicis during isometric contractions. Brain
Res 219:45–55
Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR (1999)
Control of segmental expression of the cardiac-restricted anky-
rin repeat protein gene by distinct regulatory pathways in murine
cardiogenesis. Development 126:4223–4234
Lai KM, Gonzalez M, Poueymirou WT, Kline WO, Na E, Zlotchen-
ko E, Stitt TN, Economides AN, Yancopoulos GD, Glass DJ
(2004) Conditional activation of Akt in adult skeletal muscle in-
duces rapid hypertrophy. Mol Cell Biol 24:9295–9304
Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova
E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnars-
son LG, Hughes SM, Marchand S, Sejersen T, Richard I, Ed-
strom L, Ehler E, Udd B, Gautel M (2005) The kinase domain of
titin controls muscle gene expression and protein turnover. Sci-
ence 308:1599–1603
Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur
R (2002) Myostatin inhibits myoblast diVerentiation by down-
regulating MyoD expression. J Biol Chem 277:49831–49840
Latres E, Amini AR, Amini AA, GriYths J, Martin FJ, Wei Y, Lin
HC, Yancopoulos GD, Glass DJ (2005) Insulin-like growth fac-
tor-1 (IGF-1) inversely regulates atrophy-induced genes via the
phosphatidylinositol 3-kinase/Akt/mammalian target of rapa-
mycin (PI3K/Akt/mTOR) pathway. J Biol Chem 280:2737–2744
Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J,
Price SR, Mitch WE, Goldberg AL (2004) Multiple types of skel-
etal muscle atrophy involve a common program of changes in
gene expression. Faseb J 18:39–51
Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puig-
server P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spieg-
elman BM (2002) Transcriptional co-activator PGC-1 drives
the formation of slow-twitch muscle Wbres. Nature 418:797–801
Long YC, Widegren U, Zierath JR (2004) Exercise-induced mito-
gen-activated protein kinase signalling in skeletal muscle. Proc
Nutr Soc 63:227–232
Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rass-
oulzadegan M, Grimaldi PA (2003) Peroxisome proliferator-
activated receptor delta controls muscle development and oxida-
tive capability. Faseb J 17:2299–2301
Lynn R, Morgan DL (1994) Decline running produces more sarco-
meres in rat vastus intermedius muscle Wbers than does incline
running. J Appl Physiol 77:1439–1444
Lynn R, Talbot JA, Morgan DL (1998) DiVerences in rat skeletal
muscles after incline and decline running. J Appl Physiol 85:98–
104
MacDougall JD, Sale DG, Alway SE, Sutton JR (1984) Muscle Wber
number in biceps brachii in bodybuilders and control subjects. J
Appl Physiol 57:1399–1403
MacDougall JD, Gibala MJ, Tarnopolsky MA, MacDonald JR, In-
terisano SA, Yarasheski KE (1995) The time course for elevated
muscle protein synthesis following heavy resistance exercise. Can
J Appl Physiol 20:480–486
Machida S, Spangenburg EE, Booth FW (2003) Forkhead transcrip-
tion factor FoxO1 transduces insulin-like growth factor’s signal
to p27Kip1 in primary skeletal muscle satellite cells. J Cell Phys-
iol 196:523–531
Mason SD, Howlett RA, Kim MJ, Olfert IM, Hogan MC, McNulty
W, Hickey RP, Wagner PD, Kahn CR, Giordano FJ, Johnson
RS (2004) Loss of skeletal muscle HIF-1 results in altered exer-
cise endurance. PLoS Biol 2:e288
Mauro A (1961) Satellite cell of skeletal muscle
Wbers. J Biophys Bio-
chem Cytol 9:493–495
McCall GE, Byrnes WC, Dickinson A, Pattany PM, Fleck SJ (1996)
Muscle Wber hypertrophy, hyperplasia, and capillary density in
college men after resistance training. J Appl Physiol 81:2004–2012
McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R
(2003) Myostatin negatively regulates satellite cell activation and
self-renewal. J Cell Biol 162:1135–1147
McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC
(2002) Muscle-speciWc RING Wnger-1 interacts with titin to reg-
ulate sarcomeric M-line and thick Wlament structure and may
have nuclear functions via its interaction with glucocorticoid
modulatory element binding protein-1. J Cell Biol 157:125–136
McKinnell IW, Parise G, Rudnicki MA (2005) Muscle stem cells and
regenerative myogenesis. Curr Top Dev Biol 71:113–130
McKoy G, Hou Y, Yang SY, Vega Avelaira D, Degens H, Golds-
pink G, Coulton GR (2005) Expression of Ankrd2 in fast and
slow muscles and its response to stretch are consistent with a role
in slow muscle function. J Appl Physiol 98:2337–2343
McNally EM (2004) Powerful genes - myostatin regulation of hu-
man muscle mass. N Engl J Med 350:2642–2644
McPherron AC, Lee SJ (1997) Double muscling in cattle due to
mutations in the myostatin gene. Proc Natl Acad Sci USA
94:12457–12461
McPherron AC, Lawler AM, Lee SJ (1997) Regulation of skeletal
muscle mass in mice by a new TGF- superfamily member. Na-
ture 387:83–90
Michel RN, Dunn SE, Chin ER (2004) Calcineurin and skeletal
muscle growth. Proc Nutr Soc 63:341–349
Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe
K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (2003)
The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and
DARP as a family of titin Wlament-based stress response mole-
cules. J Mol Biol 333:951–964
Milner-Brown HS, Stein RB, Yemm R (1973) The orderly recruit-
ment of human motor units during voluntary isometric contrac-
tions. J Physiol (Lond) 230:359–370
Miro O, Pedrol E, Cebrian M, Masanes F, Casademont J, Mallolas
J, Grau JM (1997) Skeletal muscle studies in patients with HIV-
related wasting syndrome. J Neurol Sci 150:153–159
Monster AW, Chan H (1977) Isometric force production by motor
units of extensor digitorum communis muscle in man. J Neuro-
physiol 40:1432–1443
Moore DR, Burgomaster KA, SchoWeld LM, Gibala MJ, Sale DG,
Phillips SM (2004) Neuromuscular adaptations in human mus-
cle following low intensity resistance training with vascular
occlusion. Eur J Appl Physiol 92:399–406
Morgan DL (1990) New insights into the behavior of muscle during
active lengthening. Biophys J 57:209–221
662
Morgan DL, Proske U (2004) Popping sarcomere hypothesis ex-
plains stretch-induced muscle damage. Clin Exp Pharmacol
Physiol 31:541–545
Morgan DL, Talbot JA (2002) The addition of sarcomeres in series
is the main protective mechanism following eccentric exercise. J
Mech Med Biol 2:421–431
Moss FP, Leblond CP (1971) Satellite cells as the source of nuclei in
muscles of growing rats. Anat Rec 170:421–435
Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G,
Molinaro M, Barton ER, Sweeney HL, Rosenthal N (2001)
Localized Igf-1 transgene expression sustains hypertrophy and
regeneration in senescent skeletal muscle. Nat Genet 27:195–200
Nader GA (2005) Molecular determinants of skeletal muscle mass:
getting the “AKT” together. Int J Biochem Cell Biol 37:1985–
1996
Nardone A, Schieppati M (1988) Shift of activity from slow to fast
muscle during voluntary lengthening contractions of the triceps
surae muscles in humans. J Physiol (Lond) 395:363–381
Nardone A, Romano C, Schieppati M (1989) Selective recruitment
of high-threshold human motor units during voluntary isotonic
lengthening of active muscles. J Physiol (Lond) 409:451–471
Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson
EN (2000) Stimulation of slow skeletal muscle Wber gene expres-
sion by calcineurin in vivo. J Biol Chem 275:4545–4548
Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafs-
son T (2004) PGC-1alpha mRNA expression is inXuenced by
metabolic perturbation in exercising human skeletal muscle. J
Appl Physiol 96:189–194
Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, SchiaVino
S (2002) A protein kinase B-dependent and rapamycin-sensitive
pathway controls skeletal muscle growth but not Wber type spec-
iWcation. Proc Natl Acad Sci USA 99:9213–9218
Paul AC (2001) Muscle length aVects the architecture and pattern of
innervation diVerently in leg muscles of mouse, guinea pig, and
rabbit compared to those of human and monkey muscles. Anat
Rec 262:301–309
Paul AC, Rosenthal N (2002) DiVerent modes of hypertrophy in
skeletal muscle Wbers. J Cell Biol 156:751–760
Pette D, Staron RS (2000) Myosin isoforms, muscle Wber types, and
transitions. Microsc Res Tech 50:500–509
Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR (1997)
Mixed muscle protein synthesis and breakdown after resistance
exercise in humans. Am J Physiol 273:E99–E107
Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient
transcriptional activation of the PGC-1 gene in human skeletal
muscle. J Physiol (Lond) 546:851–858
Prado LG, Makarenko I, Andresen C, Kruger M, Opitz CA, Linke
WA (2005) Isoform diversity of giant proteins in relation to pas-
sive and active contractile properties of rabbit skeletal muscles. J
Gen Physiol 126:461–480
Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW (2004)
Control of the size of the human muscle mass. Annu Rev Physiol
66:799–828
Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner
PD (1995) Myoglobin O
2
desaturation during exercise. Evidence
of limited O
2
transport. J Clin Invest 96:1916–1926
Richardson RS, Newcomer SC, Noyszewski EA (2001) Skeletal
muscle intracellular PO
2
assessed by myoglobin desaturation: re-
sponse to graded exercise. J Appl Physiol 91:2679–2685
Rosenblatt JD, Parry DJ (1992) Gamma irradiation prevents com-
pensatory hypertrophy of overloaded mouse extensor digitorum
longus muscle. J Appl Physiol 73:2538–2543
Roth SM, Martel GF, Ivey FM, Lemmer JT, Tracy BL, Metter EJ,
Hurley BF, Rogers MA (2001) Skeletal muscle satellite cell char-
acteristics in young and older men and women after heavy resis-
tance strength training. J Gerontol A Biol Sci Med Sci 56:B240–
B247
Sakamoto K, Aschenbach WG, Hirshman MF, Goodyear LJ (2003)
Akt signaling in skeletal muscle: regulation by exercise and pas-
sive stretch. Am J Physiol Endocrinol Metab 285:E1081–E1081
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A,
Walsh K, SchiaVino S, Lecker SH, Goldberg AL (2004) Foxo
transcription factors induce the atrophy-related ubiquitin ligase
atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412
Sartorelli V, Fulco M (2004) Molecular and cellular determinants of
skeletal muscle atrophy and hypertrophy. Sci STKE 2004:re11
SchiaVino S, Bormioli SP, Aloisi M (1976) The fate of newly formed
satellite cells during compensatory muscle hypertrophy. Virch-
ows Arch B Cell Pathol 21:113–118
SchiaVino S, Bormioli SP, Aloisi M (1979) Fibre branching and for-
mation of new Wbres during compensatory muscle hypertrophy.
In: Mauro A (ed) Muscle regeneration. Raven, New York, pp
177–188
Schmalbruch H, Lewis DM (2000) Dynamics of nuclei of muscle
Wbers and connective tissue cells in normal and denervated rat
muscles. Muscle Nerve 23:617–626
Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W,
Braun T, Tobin JF, Lee SJ (2004) Myostatin mutation associated
with gross muscle hypertrophy in a child. N Engl J Med
350:2682–2688
Schultz E, Gibson MC, Champion T (1978) Satellite cells are mitot-
ically quiescent in mature mouse muscle: an EM and radioauto-
graphic study. J Exp Zool 206:451–456
Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Har-
vey RP, Graham RM (1999) Skeletal muscle hypertrophy is
mediated by a Ca
2+
-dependent calcineurin signalling pathway.
Nature 400:576–581
Sheehan SM, Allen RE (1999) Skeletal muscle satellite cell prolifer-
ation in response to members of the Wbroblast growth factor
family and hepatocyte growth factor. J Cell Physiol 181:499–506
Shepstone TN, Tang JE, Dallaire S, Schuenke MD, Staron RS, Phil-
lips SM (2005) Short-term high- vs. low-velocity isokinetic
lengthening training results in greater hypertrophy of the elbow
Xexors in young men. J Appl Physiol 98:1768–1776
Snow MH (1990) Satellite cell response in rat soleus muscle under-
going hypertrophy due to surgical ablation of synergists. Anat
Rec 227:437–446
Spangenburg EE, Booth FW (2003) Molecular regulation of indi-
vidual skeletal muscle Wbre types. Acta Physiol Scand 178:413–
424
St-Amand J, Okamura K, Matsumoto K, Shimizu S, Sogawa Y
(2001) Characterization of control and immobilized skeletal
muscle: an overview from genetic engineering. Faseb J 15:684–
692
Stein T, Schluter M, Galante A, Soteropoulos P, Tolias P, Grinde-
land R, Moran M, Wang T, Polansky M, Wade C (2002) Energy
metabolism pathways in rat muscle under conditions of simu-
lated microgravity. J Nutr Biochem 13:471–478
Stevenson EJ, Giresi PG, Koncarevic A, Kandarian SC (2003) Glo-
bal analysis of gene expression patterns during disuse atrophy in
rat skeletal muscle. J Physiol (Lond) 551:33–48
Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO,
Gonzalez M, Yancopoulos GD, Glass DJ (2004) The IGF-1/
PI3K/Akt pathway prevents expression of muscle atrophy-in-
duced ubiquitin ligases by inhibiting FOXO transcription fac-
tors. Mol Cell 14:395–403
Tabary JC, Tabary C, Tardieu C, Tardieu G, Goldspink G (1972)
Physiological and structural changes in the cat’s soleus muscle
due to immobilization at diVerent lengths by plaster casts. J
Physiol 224:231–244
Tabary JC, Tardieu C, Tardieu G, Tabary C, Gagnard L (1976)
Functional adaptation of sarcomere number of normal cat mus-
cle. J Physiol (Paris) 72:277–291
Takahashi A, Kureishi Y, Yang J, Luo Z, Guo K, Mukhopadhyay
D, Ivashchenko Y, Branellec D, Walsh K (2002) Myogenic Akt
signaling regulates blood vessel recruitment during myoWber
growth. Mol Cell Biol 22:4803–4814
Takarada Y, Sato Y, Ishii N (2002) EVects of resistance exercise
combined with vascular occlusion on muscle function in athletes.
Eur J Appl Physiol 86:308–314
Takarada Y, Tsuruta T, Ishii N (2004) Cooperative eVects of exer-
cise and occlusive stimuli on muscular function in low-intensity
resistance exercise with moderate vascular occlusion. Jpn J Phys-
iol 54:585–592
663
Talmadge RJ, Roy RR, Edgerton VR (1996) Distribution of myosin
heavy chain isoforms in non-weight-bearing rat soleus muscle
Wbers. J Appl Physiol 81:2540–2546
Tanji J, Kato M (1973) Recruitment of motor units in voluntary
contraction of a Wnger muscle in man. Exp Neurol 40:759–770
Tardieu C, Tabary JC, Tabary C, Huet de la Tour E (1977) Compar-
ison of the sarcomere number adaptation in young and adult ani-
mals. InXuence of tendon adaptation. J Physiol (Paris) 73:1045–
1055
Tardieu C, Tabary JC, Tabary C, Tardieu G (1982) Adaptation of
connective tissue length to immobilization in the lengthened and
shortened positions in cat soleus muscle. J Physiol (Paris)
78:214–220
Tatsumi R, Allen RE (2004) Active hepatocyte growth factor is pres-
ent in skeletal muscle extracellular matrix. Muscle Nerve 30:654–
658
Tatsumi R, Anderson JE, Nevoret CJ, Halevy O, Allen RE (1998)
HGF/SF is present in normal adult skeletal muscle and is capa-
ble of activating satellite cells. Dev Biol 194:114–128
Tatsumi R, Sheehan SM, Iwasaki H, Hattori A, Allen RE (2001)
Mechanical stretch induces activation of skeletal muscle satellite
cells in vitro. Exp Cell Res 267:107–114
Tatsumi R, Hattori A, Ikeuchi Y, Anderson JE, Allen RE (2002) Re-
lease of hepatocyte growth factor from mechanically stretched
skeletal muscle satellite cells and role of pH and nitric oxide. Mol
Biol Cell 13:2909–2918
Telley IA, Denoth J, Stussi E, PWtzer G, Stehle R (2006a) Half-sar-
comere dynamics in myoWbrils during activation and relaxation
studied by tracking Xuorescent markers. Biophys J 90:514–530
Telley IA, Stehle R, Ranatunga KW, PWtzer G, Stussi E, Denoth J
(2006b) Dynamic behaviour of half-sarcomeres during and after
stretch in activated psoas myoWbrils: sarcomere asymmetry but
no “sarcomere popping”. J Physiol (Lond) 573:173–185
Thomason DB, Booth FW (1990) Atrophy of the soleus muscle by
hindlimb unweighting. J Appl Physiol 68:1–12
Thomis MA, Huygens W, Heuninckx S, Chagnon M, Maes HH,
Claessens AL, Vlietinck R, Bouchard C, Beunen GP (2004)
Exploration of myostatin polymorphisms and the angiotensin-
converting enzyme insertion/deletion genotype in responses of
human muscle to strength training. Eur J Appl Physiol 92:267–
274
Thompson PD, Moyna N, Seip R, Price T, Clarkson P, Angelopou-
los T, Gordon P, Pescatello L, Visich P, Zoeller R, Devaney JM,
Gordish H, Bilbie S, HoVman EP (2004) Functional polymor-
phisms associated with human muscle size and strength. Med Sci
Sports Exerc 36:1132–1139
Tidball JG (2005) Mechanical signal transduction in skeletal muscle
growth and adaptation. J Appl Physiol 98:1900–1908
Toigo M, Donohoe S, Sperrazzo G, Jarrold B, Wang F, Hinkle R,
Dolan E, Isfort RJ, Aebersold R (2005) ICAT-MS-MS time
course analysis of atrophying mouse skeletal muscle cytosolic
subproteome. Mol BioSyst 1:229–241
Vedsted P, Blangsted AK, Sogaard K, Orizio C, Sjogaard G (2006)
Muscle tissue oxygenation, pressure, electrical, and mechanical
responses during dynamic and static voluntary contractions. Eur
J Appl Physiol 96:165–177
Vierck J, O’Reilly B, Hossner K, Antonio J, Byrne K, Bucci L, Dod-
son M (2000) Satellite cell regulation following myotrauma
caused by resistance exercise. Cell Biol Int 24:263–272
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase
AKT pathway in human cancer. Nat Rev Cancer 2:489–501
Vollestad NK, Blom PC (1985) EVect of varying exercise intensity
on glycogen depletion in human muscle Wbres. Acta Physiol
Scand 125:395–405
Vollestad NK, Vaage O, Hermansen L (1984) Muscle glycogen
depletion patterns in type I and subgroups of type II Wbres dur-
ing prolonged severe exercise in man. Acta Physiol Scand
122:433–441
Vollestad NK, Tabata I, Medbo JI (1992) Glycogen breakdown in
diVerent human muscle Wbre types during exhaustive exercise of
short duration. Acta Physiol Scand 144:135–141
Wada KI, Katsuta S, Soya H (2003) Natural occurrence of myoWber
cytoplasmic enlargement accompanied by decrease in myonucle-
ar number. Jpn J Physiol 53:145–150
Wadley GD, Lee-Young RS, Canny BJ, Wasuntarawat C, Chen ZP,
Hargreaves M, Kemp BE, McConell GK (2006) EVect of exer-
cise intensity and hypoxia on skeletal muscle AMPK signaling
and substrate metabolism in humans. Am J Physiol Endocrinol
Metab 290:E694–E702
Wagers AJ, Conboy IM (2005) Cellular and molecular signatures of
muscle regeneration: current concepts and controversies in adult
myogenesis. Cell 122:659–667
Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM
(2003) Peroxisome-proliferator-activated receptor delta acti-
vates fat metabolism to prevent obesity. Cell 113:159–170
Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-
Ocampo CR, Ham J, Kang H, Evans RM (2004) Regulation of
muscle Wber type and running endurance by PPAR. PLoS Biol
2:e294
Wenger RH, Stiehl DP, Camenisch G (2005) Integration of oxygen
signaling at the consensus HRE. Sci STKE 2005:re12
Widegren U, Wretman C, Lionikas A, Hedin G, Henriksson J (2000)
InXuence of exercise intensity on ERK/MAP kinase signalling in
human skeletal muscle. PXugers Arch 441:317–322
Williams PE, Goldspink G (1971) Longitudinal growth of striated
muscle Wbres. J Cell Sci 9:751–767
Williams PE, Goldspink G (1984) Connective tissue changes in im-
mobilised muscle. J Anat 138(Pt 2):343–350
Winder WW (2001) Energy-sensing and signaling by AMP-acti-
vated protein kinase in skeletal muscle. J Appl Physiol 91:1017–
1028
Wittwer M, Fluck M, Hoppeler H, Muller S, Desplanches D, Billeter
R (2002) Prolonged unloading of rat soleus muscle causes dis-
tinct adaptations of the gene proWle. Faseb J 16:884–886
Wozniak AC, Pilipowicz O, Yablonka-Reuveni Z, Greenway S, Cra-
ven S, Scott E, Anderson JE (2003) C-Met expression and
mechanical activation of satellite cells on cultured muscle Wbers.
J Histochem Cytochem 51:1437–1445
Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-
Duby R, Williams RS (2002) Regulation of mitochondrial bio-
genesis in skeletal muscle by CaMK. Science 296:349–352
Yang SY, Goldspink G (2002) DiVerent roles of the IGF-I Ec pep-
tide (MGF) and mature IGF-I in myoblast proliferation and
diVerentiation. FEBS Lett 522:156–160
Yang S, Alnaqeeb M, Simpson H, Goldspink G (1996) Cloning and
characterization of an IGF-1 isoform expressed in skeletal mus-
cle subjected to stretch. J Muscle Res Cell Motil 17:487–495
Zehr EP, Sale DG (1994) Ballistic movement: muscle activation and
neuromuscular adaptation. Can J Appl Physiol 19:363–378
Zhong H, Roy RR, Siengthai B, Edgerton VR (2005) EVects of inac-
tivity on Wber size and myonuclear number in rat soleus muscle.
J Appl Physiol 99:1494–1499
