A Mechanistic Approach to Blood Flow Occlusion

Abstract

Low-Intensity occlusion training provides a unique beneficial training mode for promoting muscle hypertrophy. Training at intensities as low as 20% 1RM with moderate vascular occlusion results in muscle hypertrophy in as little as three weeks. The primary mechanisms by which occlusion training is thought to stimulate growth include, metabolic accumulation, which stimulates a subsequent increase in anabolic growth factors, fast-twitch fiber recruitment (FT), and increased protein synthesis through the mammalian target of rapamycin (mTOR) pathway. Heat shock proteins, Nitric oxide synthase-1 (NOS-1) and Myostatin have also been shown to be affected by an occlusion stimulus. In conclusion, low-intensity occlusion training appears to work through a variety of mechanisms. The research behind these mechanisms is incomplete thus far, and requires further examination, primarily to identify the actual metabolite responsible for the increase in GH with occlusion, and determine which mechanisms are associated to a greater degree with the hypertrophic/anti-catabolic changes seen with blood flow restriction.

Full text

Review 1
Loenneke JP et al. A Mechanistic Approach to Blood Flow … Int J Sports Med 2010; 31: 1 – 4
accepted after revision
August 17, 2009
Bibliography
DOI http://dx.doi.org/
10.1055/s-0029-1239499
Published online:
November 2, 2009
Int J Sports Med 2010; 31:
1 – 4 © Georg Thieme
Verlag KG Stuttgart · New York
ISSN 0172-4622
Correspondence
J. P. Loenneke
Southeast Missouri State
University Health, Human
Performance and Recreation
One University Plaza
63701 Cape Girardeau
United States
Tel.: 573-450-2952
Fax: 573-651-5150
jploenneke1s@semo.edu
Key words
● ▶ HSP 72
● ▶ growth hormone
● ▶ lactate
● ▶ mTOR
● ▶ hypertrophy
● ▶ myostatin
A Mechanistic Approach to Blood Flow Occlusion
rehabilitation, specifi cally ACL injuries, cardiac
rehabilitation patients, the elderly [33, 36] and
even astronauts [12] . Although muscle hypertro-
phy would likely benefi t those special populations,
more research should be done to further our
understanding of the proposed benefi ts to each.
The primary mechanisms by which occlusion
training stimulates growth include: metabolic
accumulation which stimulates a subsequent
increase in anabolic growth factors, fast-twitch
fi ber recruitment (FT), and increased protein
synthesis through the mammalian target of
rapamycin (mTOR) pathway. Increases in heat
shock proteins (HSP), Nitric oxide synthase-1
(NOS-1), and decreased expression of Myostatin
have also been observed [15] . The purpose of this
manuscript is to describe the physiologic mecha-
nisms by which vascular occlusion leads to skel-
etal muscle hypertrophy.
Metabolic Accumulation and Growth
Hormone
&
Whole blood lactate [8, 34] , plasma lactate
[7, 28, 33] and muscle cell lactate [14, 15] are all
increased in response to exercise with blood fl ow
Introduction
&
The American College of Sports Medicine (ACSM)
recommends lifting a weight of at least 65 % of
one ’ s one repetition maximum (1RM) to achieve
muscular hypertrophy under normal conditions.
It is believed that anything below this intensity
rarely produces substantial muscle hypertrophy
or strength gains [17] . However, some individu-
als are unable to withstand the high mechanical
stress placed upon the joints during heavy resist-
ance training. Therefore, scientists have sought
lower intensity alternatives such as blood occlu-
sion training, also known as KAATSU training.
Blood occlusion training, as the name implies,
involves decreasing blood fl ow to a muscle, by
application of a wrapping device, such as a blood
pressure cuff . Evidence indicates that this style of
training can provide a unique, benefi cial mode of
exercise in clinical settings, as it produces posi-
tive training adaptations at the equivalent to
physical activity of daily life (10 – 30 % of maximal
work capacity) [1] . Muscle hypertrophy has
recently been shown to occur during exercise as
low as 20 % of 1RM with moderate vascular occlu-
sion ( ~ 100 mmHg) [32] , which could be quite ben-
efi cial to athletes [34] , patients in post operation
Authors J. P. Loenneke
1 , G. J. Wilson
2 , J. M. Wilson
3
Affi liations 1 Southeast Missouri State University, Health, Human Performance, and Recreation, Cape Girardeau, United States
2 University of Illinois, Division of Nutritional Sciences, Champaign-Urbana, United States
3 Florida State University, Department of Nutrition, Food, and Exercise Science, Tallahassee, United States
Abstract
&
Low-Intensity occlusion training provides a
unique benefi cial training mode for promoting
muscle hypertrophy. Training at intensities as
low as 20 % 1RM with moderate vascular occlu-
sion results in muscle hypertrophy in as little as
three weeks. The primary mechanisms by which
occlusion training is thought to stimulate growth
include, metabolic accumulation, which stimu-
lates a subsequent increase in anabolic growth
factors, fast-twitch fi ber recruitment (FT), and
increased protein synthesis through the mam-
malian target of rapamycin (mTOR) pathway.
Heat shock proteins, Nitric oxide synthase-1
(NOS-1) and Myostatin have also been shown to
be aff ected by an occlusion stimulus. In conclu-
sion, low-intensity occlusion training appears
to work through a variety of mechanisms. The
research behind these mechanisms is incomplete
thus far, and requires further examination, pri-
marily to identify the actual metabolite respon-
sible for the increase in GH with occlusion, and
determine which mechanisms are associated to a
greater degree with the hypertrophic / anti-cata-
bolic changes seen with blood fl ow restriction.
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Loenneke JP et al. A Mechanistic Approach to Blood Flow … Int J Sports Med 2010; 31: 1 – 4
restriction. This is signifi cant, as growth hormone (GH) has
shown to be stimulated by an acidic intramuscular environment
[34] . Evidence indicates that a low pH stimulates sympathetic
nerve activity through a chemoreceptive refl ex mediated by
intramuscular metaboreceptors and group III and IV aff erent fi b-
ers [38] . Consequently, this same pathway has recently been
shown to play an important role in the regulation of hypophy-
seal secretion of GH [9, 38] .
However, changes in blood lactate are not always predictive of
changes in GH. To illustrate, Reeves et al. [28] showed that while
occlusion training resulted in a greater GH response than a non-
occluded control, there were no signifi cant diff erences in blood
lactate concentrations between groups. One possibility for the
disparity is that occluding blood fl ow resulted in a slower diff u-
sion of lactate out of muscle tissue, resulting in a more pro-
nounced intramuscular acidic environment and therefore, a
greater local stimulation of group IV aff erents prior to its diff u-
sion out of the cell. It is also possible that additional intramuscu-
lar metabolites stimulated changes in GH as group III and IV
aff erents are sensitive to changes in adenosine, K + , H + , hypoxia,
and AMP. Increases in these metabolites during exercise is
thought to drive the pressor refl ex leading to increased heart
rate and blood pressure, and it is postulated that this may also
facilitate increases in GH following occlusion training [27] .
Although there is no evidence that GH enhances muscle protein
synthesis when combined with traditional resistance exercise in
humans [40] , occlusion training may be diff erent. Occlusion
training elevates GH to levels over that seen with traditional
resistance training [18, 19] . One study showed an increase in GH
~ 290 times greater than baseline measurements [34] . Research
on the eff ects of supraphysiologic dosing of GH with traditional
resistance training in humans is limited. And while this research
has not yet demonstrated increased hypertrophy, it does appear
to indicate that GH administration elevates both the liver iso-
form of IGF-1 (Ea) in muscle as well as mechano-growth factor
[6] . More recently Ehrenborg and Rosen [6] have in an extensive
analysis of the literature on GH concluded that the majority of
the improvement with GH is due to the stimulation of collagen
synthesis which could provide a protective eff ect in transferring
force from skeletal muscle externally and thus protect against
ruptures.
It is unclear if IGF-1 activity is increased in response to occlusion
training. More specifi cally, Takano et al. [33] found a signifi cant
increase, whereas two other studies found no increase [1, 15] .
Possible reasons as to why there was no increase could be related
to the low intensity of the exercise. Kawada and Ishii [15] postu-
late that IGF-1 may not be necessary for muscle hypertrophy
when other factors such as Myostatin, heat shock protein 72
(HSP-72), and nitric oxide synthase-1 (NOS-1) are changed in
favor of muscle growth.
Fiber Type Recruitment
&
The size principle suggests that under normal conditions slow
twitch fi bers (ST) are recruited fi rst and as the intensity increases,
fast twitch fi bers (FT) are recruited as needed. The novel aspect
of occlusion training is that FT are recruited even though the
training intensity is low. Moritani et al. [25] postulated that
since the availability of oxygen is severely reduced during occlu-
sion, that a progressive recruitment of additional motor units
(MU) may take place to compensate for the defi cit in force devel-
opment. Previous studies have shown signifi cant increases in
MU fi ring rate and MU spike amplitude associated with arterial
occlusion suggesting that the recruitment of high threshold MU
is not only aff ected by the force and speed of contraction but also
the availability of oxygen [11, 13, 24] . Results from the use of
Integrated electromyography (iEMG) are consistent with these
fi ndings, demonstrating no practical diff erence in iEMG activity
between low intensity occlusion and high intensity non occlu-
sion training suggesting that a greater number of FT fi bers are
activated at low intensities [34 – 36] .
mTOR Pathway
&
Increased rates of protein synthesis help to drive the skeletal
muscle hypertrophy response [39] . S6K1 phosphorylation – a
critical regulator of exercise-induced muscle protein synthesis
– has been demonstrated to increase with occlusion training.
Phosphorylation of S6K1 at Thr389 was increased by three-fold
immediately post exercise with occlusion training, and remained
elevated relative to control at three hours post exercise [7] .
Moreover research demonstrates that REDD1 (regulated in
development and DNA damage responses), which is normally
expressed in states of hypoxia, is not increased in response to
occlusion training even though hypoxia-inducible factor-1 alpha
(HIF-1 α ) is elevated. Normally HIF-1 α mRNA expression corre-
lates with a corresponding elevation in REDD1 [5] . The lack of
increases in REDD1 mRNA expression may prove to be impor-
tant as REDD1 works to reduce protein synthesis through inhibi-
tion of the mammalian target of rapamycin (mTOR), responsible
for the regulation of translation initiation [5] .
Currently there is no clear explanation for this paradox. How-
ever it is conceivable that an unknown factor is increased with
occlusion training, which infl uences the transcription of HIF-1 α
and REDD1.
Heat Shock Proteins
&
HSPs are induced by stressors such as heat, ischemia, hypoxia,
free radicals, and act as chaperones to prevent misfolding or
aggregation of proteins. HSPs also appears useful to slowing
atrophy [15] , as HSP-72 plays a protective role in preventing pro-
tein degradation during periods of reduced contractile activity
[26] , by inhibiting key atrophy signaling pathways [4, 31] . The
primary pathway involved in mediating protein degradation is
the ubiquitin proteasome pathway. Recent in vivo data, demon-
strate that increased levels of HSP-70 is suffi cient to prevent
skeletal muscle disuse atrophy by inhibiting the promoter acti-
vation of atrogin-1 / muscle atrophy F-box (MAFbx) and muscle-
specifi c RING fi nger 1 (MuRF1) as well as the transcription
factors which regulate their expression, forkhead box O (Foxo)
and nuclear factor of P + NF-P + . Senf et al. [4] also observed that
Foxo3a, a member of the Foxo family upregulated during atro-
phy, not NF-P + is necessary for the increase in MAFbx and
MuRF1 promoter activities during disuse. Regardless both tran-
scriptional factor activities, Foxo and NF-P + are inhibited with
elevated HSP-70 levels. Incidentally, occlusion training has been
shown to increase HSP-72 in a rat model [15] , and Kawada and
Ishii [15] postulated that the increase in HSP-72 could be a
potential mechanism by which occlusion increases skeletal mus-
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Loenneke JP et al. A Mechanistic Approach to Blood Flow … Int J Sports Med 2010; 31: 1 – 4
cle hypertrophy and attenuates atrophy [36] , likely by inhibiting
the mediating pathways of the ubiquitin proteasome pathway.
NOS-1
&
Nitric oxide synthase is an enzyme responsible for converting
L-arginine into nitric oxide (NO), a small and electrically neutral
molecule capable of moving with ease through tissues [3] . Neu-
ronal NOS (nNOS) is found in the transmembrane / dystrophin
protein complex of skeletal muscle [29] . At rest, nNOS continu-
ally produces low levels of NO which appear to maintain satellite
cell quiescence. During exercise-induced contraction nNOS is
thought to be activated by mechanical shear forces, as well as
increased intracellular Ca
2 + concentrations [37] . nNOS is
increased in conjunction with occlusion training, possibly medi-
ated by the increased fl ux of Ca
2 + , as well as reperfusion [15] .
According to Anderson et al., [2, 3] a spike in NO production trig-
gers the release of hepatocyte growth factor (HGF) from its bind-
ing to the muscle extracellular matrix followed by co-localization
with its c-MET receptor on satellite cells leading to their activa-
tion. This model is supported by a number of fi ndings demon-
strating the inhibition of satellite cells in response to short-term
L-arginine methyl ester (L-NAME) treatment following injury or
mechanical stretch [3] .
Interestingly, Kawada and Ishii [15] did not show an increase in
NO, only nNOS, which could be due to the short life span of NO.
In this study, NO concentration was measured indirectly by its
oxidation products, therefore the obtained values might have
resulted from the production and breakdown of NO, both of
which might be infl uenced by the occlusion of blood fl ow.
Myostatin
&
Myostatin is a negative regulator of muscle growth and muta-
tions of this gene result in overgrowth of musculature in mice,
cattle, and humans [21, 22, 30] . Myostatin appears to inhibit sat-
ellite cell proliferation because Myostatin-null mice display
muscle hypertrophy and increased postnatal muscle growth,
which have been linked to increase satellite cell activity
[10, 20, 23] . McCroskery et al. [20] conclude that Myostatin is
expressed in adult satellite cells and that Myostatin regulates
satellite cell quiescence and self-renewal, showing it does play a
role in adult myogenesis.
Muscle Myostatin gene expression has been shown to decrease
as a result of mechanical overloading [16] , as well as in low
intensity exercise with occlusion [15] . Occlusion may cause
favorable hypertrophic changes in Myostatin as a result of
hypoxia and / or the accumulation of metabolic subproducts.
Conclusion
&
In conclusion low-intensity occlusion training works through a
variety of mechanisms, with the most prominent being meta-
bolic accumulation, fi ber type activation, and mTOR signaling.
The research behind these mechanisms is incomplete thus far,
and more studies should be included to elucidate the actual
metabolite(s) responsible for the increase in GH with occlusion.
Furthermore, research should be directed towards determining
which particular mechanism(s) is associated to a greater degree
with the hypertrophic / anti-catabolic changes seen with blood
fl ow restriction. While we have a base foundation of possibili-
ties, controlled studies addressing each proposed mechanism
Fig. 1 Mechanisms by which blood occlusion training increases strength and muscular Hypertrophy. Arrows indicate stimulation, and blocked lines
indicate inhibition. HSP = Heat shock proteins, GH = Growth Hormone, NO = Nitric oxide, IGF-1 = Insulin like growth factor, GHRH = Growth Hormone
Releasing Hormone.
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Loenneke JP et al. A Mechanistic Approach to Blood Flow … Int J Sports Med 2010; 31: 1 – 4
would provide a better understanding of each. For example, the
paradox of REDD1 and HIF-1 α should be examined to determine
if there is another factor that is increased in response to blood
fl ow restriction. As postulated earlier, perhaps there is an
unknown factor that infl uences the transcription of HIF-1 α and
REDD1 leading to the paradoxical increase in HIF-1 α with a
decrease in REDD1 expression. HSPs may also play an important
role, specifi cally in attenuating skeletal muscle atrophy. While
animal studies show promise, human studies should be per-
formed to try and confi rm the initial fi ndings of Kawada and
Ishii.
The mechanisms described in this paper have all been shown to
potentially induce skeletal muscle hypertrophy in response to
blood-fl ow restriction. Although some mechanisms may be
more prominent than others, all the mechanisms described
likely play at least some part in the enhanced skeletal muscle
hypertrophy response associated with occlusion training.
●
▶ Fig. 1 summarizes the mechanisms by which blood occlusion
training may stimulate muscular hypertrophy.
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