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Sleep and muscle recovery: Endocrinological and molecular basis for a new
and promising hypothesis
M. Dattilo
, H.K.M. Antunes
, A. Medeiros
, M. Mônico Neto
, H.S. Souza
, S. Tufik
, M.T. de Mello
Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil
Centro de Estudos em Psicobiologia e Exercício (CEPE), São Paulo, Brazil
Departamento de Biociências, Universidade Federal de São Paulo, Santos, Brazil
article info
Article history:
Received 13 December 2010
Accepted 10 April 2011
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.
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.
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: (M.T. de Mello).
Medical Hypotheses 77 (2011) 220–222
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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/
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
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
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.
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),
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Full-text available
Sleep loss can modify energy intake and expenditure. To determine whether sleep restriction attenuates the effect of a reduced-calorie diet on excess adiposity. Randomized, 2-period, 2-condition crossover study. University clinical research center and sleep laboratory. 10 overweight nonsmoking adults (3 women and 7 men) with a mean age of 41 years (SD, 5) and a mean body mass index of 27.4 kg/m² (SD, 2.0). 14 days of moderate caloric restriction with 8.5 or 5.5 hours of nighttime sleep opportunity. The primary measure was loss of fat and fat-free body mass. Secondary measures were changes in substrate utilization, energy expenditure, hunger, and 24-hour metabolic hormone concentrations. Sleep curtailment decreased the proportion of weight lost as fat by 55% (1.4 vs. 0.6 kg with 8.5 vs. 5.5 hours of sleep opportunity, respectively; P = 0.043) and increased the loss of fat-free body mass by 60% (1.5 vs. 2.4 kg; P = 0.002). This was accompanied by markers of enhanced neuroendocrine adaptation to caloric restriction, increased hunger, and a shift in relative substrate utilization toward oxidation of less fat. The nature of the study limited its duration and sample size. The amount of human sleep contributes to the maintenance of fat-free body mass at times of decreased energy intake. Lack of sufficient sleep may compromise the efficacy of typical dietary interventions for weight loss and related metabolic risk reduction. National Institutes of Health.
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The daily rhythm of cortisol secretion is relatively stable and primarily under the influence of the circadian clock. Nevertheless, several other factors affect hypothalamo-pituitary-adrenal (HPA) axis activity. Sleep has modest but clearly detectable modulatory effects on HPA axis activity. Sleep onset exerts an inhibitory effect on cortisol secretion while awakenings and sleep offset are accompanied by cortisol stimulation. During waking, an association between cortisol secretory bursts and indices of central arousal has also been detected. Abrupt shifts of the sleep period induce a profound disruption in the daily cortisol rhythm, while sleep deprivation and/or reduced sleep quality seem to result in a modest but functionally important activation of the axis. HPA hyperactivity is clearly associated with metabolic, cognitive and psychiatric disorders and could be involved in the well-documented associations between sleep disturbances and the risk of obesity, diabetes and cognitive dysfunction. Several clinical syndromes, such as insomnia, depression, Cushing's syndrome, sleep disordered breathing (SDB) display HPA hyperactivity, disturbed sleep, psychiatric and metabolic impairments. Further research to delineate the functional links between sleep and HPA axis activity is needed to fully understand the pathophysiology of these syndromes and to develop adequate strategies of prevention and treatment.
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Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis.
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Sleep comprises approximately one-third of a person's lifetime, but its impact on health and medical conditions remains partially unrecognized. The prevalence of sleep disorders is increasing in modern societies, with significant repercussions on people's well-being. This article reviews past and current literature on the paradoxical sleep deprivation method as well as data on its consequences to animals, ranging from behavioral changes to alterations in the gene expression. More specifically, we highlight relevant experimental studies and our group's contribution over the last three decades.
Leptin levels were stable across the daytime period under both sleep conditions, which was consistent with the fact that calories were exclusively delivered in the form of a constant glucose infusion. Average total sleep time was 9 hours and 8 minutes when the men spent 10 hours in bed and 3 hours and 53 minutes when the men spent 4 hours in bed (P < 0.01). When spending 4 hours in bed, the participants had mean leptin levels that were 18% lower (2.1 ng/mL vs. 2.6 ng/mL; P = 0.04) (Figure 1, part A) and mean ghrelin levels that were 28% higher (3.3 ng/mL vs. 2.6 ng/mL; P = 0.04) (Figure 1, part B) than when the participants spent 10 hours in bed. The ratio of the concentrations of orexigenic ghrelin to anorexigenic leptin increased by 71% (CI, 7% to 135%) with 4 hours in bed compared with 10 hours in bed. Sleep restriction relative to sleep extension was associated with a 24% increase in hunger ratings on the 10-cm visual analogue scale (P < 0.01) and a 23% increase in appetite ratings for all food categories combined (P = 0.01) (Figure 1, parts C and D, and Table 1). The increase in appetite tended to be greatest for calorie-dense foods with high carbohydrate content (sweets, salty foods, and starchy foods: increase, 33% to 45%; P = 0.06) (Table 1). The increase in appetite for fruits and vegetables was less consistent and of lesser magnitude (increase, 17% to 21%) (Table 1). Appetite for protein-rich nutrients (meat, poultry, fish, eggs, and dairy foods) was not significantly affected by sleep duration (Table 1). When we considered the changes in ghrelin and leptin in an integrated fashion by calculating the ghrelin-to-leptin ratio, the increase in hunger was proportional to the increase in ghrelin-to-leptin ratio (r = 0.87) (Figure 2). Almost 70% of the variance in increased hunger could be accounted for by the increase in the ghrelin-to-leptin ratio.
Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25-35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance.
Poor sleep has increasingly gained attention as a potential contributor to the recent obesity epidemic. The increased prevalence of obesity in Western nations over the past half-century has been paralleled by a severe reduction in sleep duration. Physiological studies suggest reduced sleep may impact hormonal regulation of appetite. Prospective studies suggest reduced habitual sleep duration as assessed by self-report is an independent risk factor for an increased rate of weight gain and incident obesity. Cross-sectional studies have demonstrated that the association between reduced sleep and obesity persists when sleep habits are measured objectively, that the association is as a result of elevations in fat and not muscle mass and that this association is not related to sleep apnoea. Thus, reduced sleep appears to represent a novel, independent risk factor for increased weight gain. Further research is needed to determine whether interventions aimed at increasing sleep may be useful in combating obesity.