sleep-and-muscle-recovery-endocrinological-and-molecular-basis-for-a-new-and-promissing-hypothesis

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Sleep and muscle recovery: Endocrinological and molecular basis for a new
and promising hypothesis
M. Dattilo
b
, H.K.M. Antunes
b,c
, A. Medeiros
c
, M. Mônico Neto
b
, H.S. Souza
b
, S. Tufik
a
, M.T. de Mello
a,b,
⇑
a
Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil
b
Centro de Estudos em Psicobiologia e Exercício (CEPE), São Paulo, Brazil
c
Departamento de Biociências, Universidade Federal de São Paulo, Santos, Brazil
article info
Article history:
Received 13 December 2010
Accepted 10 April 2011
abstract
Sleep is essential for the cellular, organic and systemic functions of an organism, with its absence being
potentially harmful to health and changing feeding behavior, glucose regulation, blood pressure, cogni-
tive processes and some hormonal axes. Among the hormonal changes, there is an increase in cortisol
(humans) and corticosterone (rats) secretion, and a reduction in testosterone and Insulin-like Growth
Factor 1, favoring the establishment of a highly proteolytic environment. Consequently, we hypothesized
that sleep debt decreases the activity of protein synthesis pathways and increases the activity of degra-
dation pathways, favoring the loss of muscle mass and thus hindering muscle recovery after damage
induced by exercise, injuries and certain conditions associated with muscle atrophy, such as sarcopenia
and cachexia.
Ó2011 Elsevier Ltd. All rights reserved.
Background
Several pieces of evidence point to sleep as an important regu-
lator of numerous biological aspects, maintaining vital physiologi-
cal functions, homeostasis, learning and memory, by promoting
the development of the central nervous system and physical recov-
ery [1,2].
However, in recent years, a reduction in the duration of sleep
time is becoming evident in the populations of industrialized coun-
tries, motivating a search for a better understanding of the poten-
tial health hazards arising from sleep debt. Studies involving both
animals and humans have shown that sleep deprivation/restriction
results in impairments in many aspects, such as cognitive [3],
immunological [4], metabolic [5,6] and hormonal [6–10] functions.
From a metabolic point of view, almost all studies performed in
humans suggest that sleep debit favors an increase in body mass
[11,12], mainly due to increased hunger and appetite [13]. In con-
trast, opposing results have been found in mice, where a marked
increase in metabolism can be observed for up to 21 days, causing
a reduction in body mass in response to protocols that employ total
deprivation of paradoxical sleep and its maintenance in the proto-
cols of sleep restriction (shorter sleep per night) [14].
Among the hormonal changes, it is worth noting that major
axes are negatively affected, including the hypothalamic–pitui-
tary–adrenal axis [9,15] and hypothalamic–pituitary–gonadal axis
[9]. In humans, total sleep deprivation is associated with two dis-
tinct outcomes: increases in the secretion of catabolic hormones,
such as cortisol [16–18], and changes in the pattern of rhythmic
secretion of anabolic hormones, such as testosterone [19]. Further-
more, sleep restriction also seems to be associated with increased
levels of cortisol, as described by Spiegel et al. [6]. It should also be
noted that significant reductions in testosterone are observed in
apneic individuals, who, despite completing seemingly adequate
periods of sleep, have clearly impaired sleep quality due to multi-
ple awakenings throughout the night [20].
The animal experiments performed by our group demonstrate
that, in rats, paradoxical sleep deprivation results in increases in
corticosterone concentrations and reductions in testosterone after
just 24 h, and that these concentrations remain altered for up to
96 h [9]. Moreover, other evidence indicates that concentrations
of Insulin-like Growth Factor 1 (IGF-1), a hormone with anabolic
properties that is secreted predominantly by the liver in response
to growth hormone, are rapidly reduced under conditions of sleep
deprivation [10].
Hormonal changes resulting from sleep deprivation/restriction
and its impact on skeletal muscle metabolism
Considering the physiological properties that the hormones tes-
tosterone, IGF-1 and cortisol/corticosterone have on the body, a
potentially catabolic and proteolytic environment may be present
in sleep debt conditions. Although this condition appears to be
associated with increased body mass in humans, the mechanisms
responsible for this association need to be better understood,
0306-9877/$ - see front matter Ó2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2011.04.017
⇑
Corresponding author. Address: Rua Professor Francisco de Castro, 93 Vila
Clementino, CEP 04020-050, São Paulo, Brazil. Tel./fax: +55 11 5572 0177.
E-mail address: tmello@demello.net.br (M.T. de Mello).
Medical Hypotheses 77 (2011) 220–222
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journal homepage: www.elsevier.com/locate/mehy

considering that individuals deprived of sleep for 72 h showed
higher urinary excretion of urea, suggesting greater muscle prote-
olysis [21]. A second piece of evidence that raises questions about
this issue is the interesting finding reported by Nedeltcheva et al.
[22], in which a 14-day calorie restricted diet caused similar reduc-
tions in body mass in people who slept either 5.5 or 8.5 h (sleep
restriction versus normal sleep, respectively). However, under
the conditions of sleep restriction, the decrease in fat mass was
55% lower and, interestingly, the loss of muscle mass was 60%
higher. This suggests that a peculiar pattern of hormone secretion
may promote different effects in modulating body composition,
and that skeletal muscle can potentially be impaired.
Considering the large number of deleterious effects observed
under conditions of sleep debt, many researchers have aimed to
better understand the molecular mechanisms involved in these sit-
uations. Thus, it is pertinent to further consider the impact of sleep
deprivation/restriction on the expression of intramuscular proteins
that are directly involved in maintaining muscle mass.
Given that body mass is maintained on the basis of an energy
balance, i.e., when energy consumption equals caloric expenditure,
maintenance of muscle mass reflects a balance between the rela-
tive rates of protein synthesis and degradation, with the predomi-
nance of synthesis favoring muscle hypertrophy (protein
accretion), while the prevalence of degradation instead results in
muscle atrophy and a loss of protein content. Moreover, the main-
tenance of skeletal muscle is tightly regulated by hormonal and
nutritional factors that, in turn, modulate the dynamic balance be-
tween anabolic (hypertrophy) and catabolic (atrophy) reactions,
thereby determining muscle protein content [23].
The theoretical foundation, pioneered by our group, for the rela-
tionship between hormonal patterns resulting from sleep depriva-
tion/restriction and reductions in protein synthesis and/or
increased proteolysis, as mediated by the expression of proteins in-
volved in the hypertrophy and atrophy pathways, is extremely
strong, plausible and promising. Therefore, the impact of sleep
deprivation/restriction on muscle metabolism observed in humans
[22] can, in part, be explained by this model. Concerning rats,
although there are no reports in the literature regarding the direct
impact of sleep deprivation/restriction on skeletal muscle, it is per-
tinent to consider that the reduction in body mass [14] is accompa-
nied by muscle atrophy.
Pathways involved in protein synthesis and degradation, and its
possible modulation in response to sleep deprivation/
restriction
IGF-1-mediated signaling is a central element in the stimulation
of muscle protein synthesis, best characterizing muscle growth and
relating to adaptive processes in skeletal muscle [24]. In muscle,
the binding of IGF-1 to its receptor promotes the activation of
phosphatidylinositol 3-kinase (PI3K) and Akt, which induces mus-
cle hypertrophy. This is primarily mediated by stimulation of pro-
tein translation via regulation of glycogen synthase kinase-3b
(GSK-3b) and mammalian Target of Rapamycin (mTOR) [25],
resulting in increased p70S6 kinase activity, a determinant of cell
size and ribosome biogenesis.
The mTOR pathway is a master positive regulator of protein
synthesis, integrating signals from growth factors, nutrients, hy-
poxia, and cellular stress, and stimulating the binding of eIF4G to
eIF4E to promote cap-dependent translation initiation [26]. More-
over, phosphorylation and activation by mTOR of p70S6 kinase is
an important determinant of cell and skeletal muscle size [27–29].
Testosterone mediates its anabolic properties by binding to
cytoplasmic androgen receptors, which migrate to the nucleus
and bind specific regulatory (promoter) sequences, thereby
increasing transcription and stimulating protein synthesis. In addi-
tion, testosterone can also indirectly promote transcription and
protein synthesis by inhibiting the activity of Regulated in Devel-
opment and DNA damage responses 1 (REDD1), a protein that
blocks the activity of mTOR [30].
Some evidence indicates that testosterone is capable of inhibit-
ing myostatin, a member of the TGF-beta superfamily that inhibits
skeletal muscle growth [31] by inhibiting satellite cell proliferation
and differentiation, a critical step in muscle recovery and growth.
This results in a downregulation of the myogenic regulatory fac-
tors, MyoD and myogenin [32–34].
Elevated levels of cortisol/corticosterone, may modulate muscle
protein metabolism because glucocorticoid-induced muscle atro-
phy is associated with both increased catabolism [35] and reduced
synthesis [36] of muscle proteins, which further potentiate the
muscular atrophy. The ubiquitin–proteosome pathway has been
linked to much of the increase in muscle protein catabolism that
occurs during atrophy [37,38]. In this pathway, ubiquitin ligases
mark proteins for degradation by covalent modification with poly-
ubiquitin chains [39]. Two muscle-specific E3 ubiquitin ligases,
muscle atrophy F-box (MAFbx; also called atrogin-1) and Muscle
RING-Finger-1 (MRF1), play important roles in muscle atrophy. An-
other mechanism for the actions of these glucocorticoids is
through up-regulation of REDD1 [40], thereby inhibiting mTOR
and p70s6 kinase and reducing protein synthesis.
Integrating these results suggests that sleep deprivation/restric-
tion results in reductions in IGF-1 and testosterone concentrations,
which may be able to decrease the activity of the IGF-1/PI3K/Akt
and mTOR pathways, also diminishing the signal inhibition for
myostatin expression, thereby promoting protein degradation.
The increase in glucocorticoid levels up-regulates REDD1, activates
the ubiquitin–proteosome system and up-regulates myostatin
expression, which further reduces the rates of protein synthesis
by increasing protein degradation and promoting muscle atrophy.
Can the process of muscle recovery be damaged by sleep
deprivation/restriction?
Sleep, and the lack thereof, should be stressed as contributing
an important role in the process of muscle recovery after certain
kinds of damage, whether induced by exercise or injury. It is well
established that muscle has highly plastic properties and is capable
of recovering from several types of damage. However, significant
molecular changes are required to allow damaged cells to recover
or be replaced by new cells, involving steps that depend on the
proliferation, fusion and differentiation of satellite cells [41]. These
Fig. 1. Schematic representation of the effects of sleep debt on skeletal muscle
metabolism.
M. Dattilo et al./ Medical Hypotheses 77 (2011) 220–222 221

processes must be accompanied by a concomitant signal of muscle
hypertrophy because the cells need to increase in volume until the
muscle fibers reach their ideal size. Such growth is dependent on
the activation of the aforementioned syntheses pathways and inhi-
bition of protein degradation pathways. It is noteworthy that these
issues are relevant to the clinical condition of sarcopenia, charac-
terized by decreased protein synthesis signaling and increased
apoptosis, which occurs in the elderly population and in the setting
of certain diseases, such as cachexia.
Thus, we hypothesize that sleep debt damages muscle physiol-
ogy and impairs muscle recovery because of increased stimulation
of protein degradation, which is detrimental to protein synthesis
and promotes muscular atrophy. Muscle recovery would poten-
tially be compromised because this process is strongly regulated
by the previously discussed anabolic and catabolic hormones,
which are strongly influenced by sleep (as detailed in Fig. 1). By
expanding our knowledge of these issues, a new field of research
can be established to investigate various strategies for minimizing
the deleterious effects arising from a lack of sleep.
Conflict of interest
None declared.
Acknowledgements
The authors thank Everald Van Cooler, Patricia Chakur Brum,
the Laboratory of Cellular and Molecular Physiology of Excercise,
School of Physical Education and Sport, University of São Paulo
(USP), and the support of the Associação Fundo de Incentivo á Pes-
quisa (AFIP), the Centro de Estudos em psicobiologia e Exercicio
Acidentes (CEPE), the Centro de Estudo Multidisciplinar em Sono-
lencia e Acidentes (CEMSA), CEPID/SONO-FAPESP (#98/14303-3),
CNPq, CAPES, FAPESP (2009/11056-1), UNIFESP, FADA, FADA/
UNIFESP.
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