Download Cellular mechanisms regulating protein synthesis and skeletal

J Appl Physiol 106: 1367–1373, 2009;
doi:10.1152/japplphysiol.91355.2008.
HIGHLIGHTED TOPIC
Review
Regulation of Protein Metabolism in Exercise and Recovery
Cellular mechanisms regulating protein synthesis and skeletal muscle
hypertrophy in animals
Mitsunori Miyazaki and Karyn A. Esser
Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky
Submitted 10 October 2008; accepted in final form 21 November 2008
mechanical stretch; REDD2; overload; IGF-1; amino acids
IT IS WIDELY ACCEPTED that repeated bouts of resistance exercise/
high-force contractions produce compensatory growth of skeletal muscle (35, 42, 47, 95). The increase in skeletal muscle
mass results from rates of protein synthesis increased more
than changes in protein degradation with the net result being an
accumulation of protein and increased fiber area (66, 96).
While the effect of resistance exercise/contraction on muscle
mass has long been recognized, the mechanisms underlying the
link between high resistance contractions and muscle growth
are, to date, not fully understood.
One of the important variables contributing to the growth
response in skeletal muscle is the application of mechanical
loading. For this review we use mechanical loading very
generally as the application of force on the muscle or muscle
cell. This force on the muscle can occur via active cross-bridge
interactions (such as during concentric, isometric, or eccentric
contractions) in a gravity-based environment or via external
application of force such as passive stretching. The most
established animal model for studying skeletal muscle hypertrophy in response to mechanical loading was described by Dr.
A. L. Goldberg (38) and was referred to as work-induced
muscle growth. This model is now commonly known as the
synergist ablation/mechanical overload model and is a surgical
model that involves cutting of the tendon and removal of the
gastrocnemius muscle, resulting in loading and compensatory
growth of the remaining plantar flexors, the plantaris, and
soleus muscles. These muscles are involved in maintenance of
Address for reprint requests and other correspondence: K. A. Esser, Dept. of
Physiology, College of Medicine, Univ. of Kentucky, 800 Rose St., UKMC
MS508, Lexington, KY 40536 (e-mail: [email protected]).
http://www. jap.org
posture and walking so are loaded by the body weight of the
animal. Muscle mass changes are fairly rapid and the growth is
robust, ranging from 40 to 200% depending on the muscle and
species studied (7, 37, 38, 53, 56). Many labs use this model in
their research programs to study molecular and cellular mechanisms associated with hypertrophy and while the extent of the
surgery varies among labs, the fundamental concept of overload remains the same (3, 6, 44).
The early papers in skeletal muscle compensatory hypertrophy established that rates of protein synthesis are enhanced by
8 h after surgery and remain elevated for over a week during
the growth response (37, 75). Consistent with studies of muscle
growth in humans, these studies in rodents illustrate that a
robust and prolonged increase in protein synthesis is associated
with the hypertrophic response to increased mechanical loading (35, 37, 85). Because of the known association between
tissue protein synthesis and hormones such as growth hormone
and insulin, Goldberg’s group (38, 40) performed studies of
muscle growth in hypophysectomized or diabetic rats. He
found that skeletal muscle hypertrophy occurs to the same
extent in the absence of circulating pituitary hormones or
insulin. In 1975, Goldberg et al. (39) proposed that increased
tension development, either passive or active, was the critical
event in initiating compensatory growth in mammals. Consistent with the role that mechanical tension plays in regulating
skeletal muscle mass in vivo, stretch models have been used to
demonstrate that mechanical tension also regulates protein
synthesis in vitro (97–99). Using a cell culture model, Vandenburgh and Kaufman (97, 98) demonstrated that intermittent stretch produces a large increase in protein synthesis
and a smaller decrease in protein degradation in avian
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Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and
skeletal muscle hypertrophy in animals. J Appl Physiol 106: 1367–1373, 2009;
doi:10.1152/japplphysiol.91355.2008.—Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Skeletal muscle is a
highly adaptable tissue with well-known sensitivities to environmental cues such as
growth factors, cytokines, nutrients, and mechanical loading. All of these factors
act at the level of the cell and signal through pathways that lead to changes in
phenotype through multiple mechanisms. In this review, we discuss the animal and
cell culture models used and the signaling mechanisms identified in understanding
regulation of protein synthesis in response to mechanical loading/resistance exercise. Particular emphasis has been placed on 1) alterations in mechanical loading
and regulation of protein synthesis in both in vivo animal studies and in vitro cell
culture studies and 2) upstream mediators regulating mammalian target of rapamycin signaling and protein synthesis during skeletal muscle hypertrophy.
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mTOR REGULATION IN SKELETAL MUSCLE
J Appl Physiol • VOL
stretched 15% of resting length for up to 90 min. The results of
these experiments found that passive stretch was sufficient to
induce increases in protein synthesis. Conditioned media experiments from these ex vivo stretch studies also suggested
that the increase in protein synthesis seen with mechanical
stretch oscillations was not due to release of growth factors
from the stretched muscle (52, 54). Taken together, the
results of the in vitro/ex vivo studies support the findings
in vivo and demonstrate that mechanical stretch/loading is
sufficient to increase rates of protein synthesis. Additionally, the results of these studies are suggestive that mechanical strain can activate protein synthesis independent of
growth factor involvement.
mTOR SIGNALING AND PROTEIN SYNTHESIS
mTOR is a serine/threonine kinase of the phosphatidylinositol kinase-related kinase family and is highly conserved from
yeast to mammals (61). mTOR signaling pathway has a wide
range of functions including regulation of protein synthesis,
cell proliferation, apoptosis, and autophagy. In mammalian
cells, mTOR exists in two distinct multi-protein complexes,
mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2).
TORC1 is a complex comprised of mTOR, regulatory associated protein of mTOR (Raptor), and G protein ␤-subunit-like
(G␤l/also known as mLST8). The TORC2 complex is comprised of mTOR, rapamycin-insensitive companion of mTOR
(Rictor), stress-activated-protein-kinase-interacting protein 1
(SIN1), and G␤l. For the purpose of this review, we will focus
on mTOR/TORC1 signaling and regulation of protein synthesis during hypertrophy in skeletal muscle.
To date, numerous studies have shown that mTOR plays a
critical role in regulating protein synthesis and cell growth/
hypertrophy in skeletal muscle (11, 36, 54, 74, 86). Consistent
with its role in regulation of protein synthesis, signaling
through mTOR occurs in muscle after high force contractions/
mechanical loading and is maintained for many hours (18 –36
h) after a single bout of loading (10). In contrast, mTOR
signaling is only transiently (⬍6 h) upregulated after low force
contractions that do not elicit growth of skeletal muscle (10,
73). Also considered in this review is that mTOR receives and
integrates many different upstream signals that can function as
either activators or inhibitors of activity and many of these
upstream regulators are known to be active in muscle following
mechanical loading. For example, activators of mTOR include
growth factors, amino acid availability, and mechanical strain,
while factors that could inhibit mTOR function include energy
stress (via AMPK-dependent regulation) and other stress response molecules (induction of REDD1/REDD2). In the following sections we provide a brief summary of known components of the mTOR signaling pathway and these are depicted
in Fig. 1. More detailed reviews of mTOR regulation can be
found elsewhere (80, 84, 108).
GROWTH FACTOR/INSULIN SIGNALING AND REGULATION
OF mTOR ACTIVITY
The most well-defined pathway regulating mTOR activity in
skeletal muscle is the IGF-1/insulin pathway. Stimulation of
muscle with growth factors (e.g., insulin and/or IGF-1) leads to
activation of phosphoinositide 3-kinase (PI3K), triggering multiple downstream signaling events associated with the control
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myotubes. These data suggest that in cell culture, like
models in vivo, the hypertrophic response to increased
mechanical tension is due, in part, to an increased rate of
protein synthesis.
Currently, the mechanisms proposed in regulation of resistance exercise/contraction-induced compensatory growth include, but are not limited to, the involvement of local growth
factors and the signaling events induced by the mechanical
stimulus (39, 66, 96, 99). Previous studies have shown that
mechanical stimulation of muscle tissue/cells results in local
release of growth factors such as fibroblast growth factor
(FGF) and insulin-like growth factor-1 (IGF-1; 1, 2, 16, 41,
101). It has also been established that mechanical loading in
skeletal muscle can induce increased expression of IGF-1 at
both the mRNA and protein levels (3). In addition, many other
studies have demonstrated that the addition of exogenous/
recombinant IGF-1 leads to an increase in protein synthesis and
skeletal muscle growth/hypertrophy both in vitro and in vivo
(4, 77, 86, 103). Transgenic mice in which IGF-1 was overexpressed only in muscle also led to increases in fiber crosssectional area and skeletal muscle mass (17, 72). The results of
these studies have led to a model in which mechanical loading
of skeletal muscle leads to production and release of IGF-1 that
functions in an autocrine/paracrine mechanism to increase
protein synthesis and growth (3, 23). However, this model has
been challenged recently by Spangenburg et al. (90) who
suggest that IGF-1 signaling is not necessary for mechanical
overload-induced muscle growth. The investigators used a
transgenic mouse overexpressing a dominant negative form of
the IGF-1 receptor in skeletal muscle. This receptor could bind
IGF-1 but is kinase inactive so does not lead to downstream
signaling (90). They demonstrated that IGF-1 and insulin
signaling through Akt/protein kinase B (PKB) was impaired
but they found that skeletal muscle hypertrophy was not altered
in response to mechanical overload. There were no differences
in mechanical overload-induced growth responses in skeletal
muscle of wild-type and transgenic mice. Furthermore, they
also demonstrated that mammalian target of rapamycin
(mTOR) signaling pathway, which was previously shown to be
necessary for skeletal muscle growth (11, 86), was activated
similarly by the overload stimulus in the muscle of both
wild-type and transgenic mice. Results of this study indicate
that activation of the IGF-1 receptor is not necessary for the
induction of muscle growth in response to increased mechanical loading in vivo.
To complement the in vivo studies, several labs have employed both in vitro cell models and ex vivo tissue models to
evaluate the contribution of mechanical loading on protein
synthesis. These models are valuable as they allow for more
defined hormonal and mechanical environments. As noted
earlier, Dr. H. H. Vandenburgh (97) performed the seminal
work in which they stretched avian myotubes in vitro and
found an increased rate of amino acid uptake, protein synthesis,
and protein accumulation. Their models included both static
stretch and stretch oscillations and clearly established biochemical links between mechanical stretch and regulation of
protein synthesis (97–100). More recently, Hornberger et al.
(54) used an ex vivo system to test the contribution of mechanical strain oscillations on the regulation of protein synthesis in mammalian muscle. Mouse extensor digitorum longus
(EDL) muscles were incubated in an organ bath and passively
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mTOR REGULATION IN SKELETAL MUSCLE
Fig. 1. Simplified scheme depicting a model through
which both positive and negative factors can contribute
to mTOR/TORC1 signaling and protein synthesis in
skeletal muscle. Activators, growth factors, amino acids, and mechanical stretch are labeled in blue while
inhibitory signals are labeled in red. Solid lines depict
defined interactions among molecules, dotted lines
indicate suggested interactions.
J Appl Physiol • VOL
sectional area in the tibialis anterior and EDL muscles compared with controls. In response to overexpression of TSC1,
TSC2 was stabilized and this was associated with significant
inhibition of mTOR signaling. Other studies in rodents have
reported that TSC2 is modified by phosphorylation at several
different sites (Ser1345 and Thr1462 sites) after ex vivo
high-frequency electrical stimulation (8) or in vivo mechanical
overload model (71). Experiments evaluating the mRNA levels
of TSC1, TSC2, and Rheb were recently reported from human
muscle biopsies following one bout of high-resistance contractions and nutritional supplements. Drummond et al. (27) found
that mRNA levels of TSC1 and TSC2 (negative regulators of
mTOR) were decreased and Rheb (positive regulator of
mTOR) was increased at 6 h after single bout of resistance
exercise in young subjects. While limited, these findings support the likely contribution of the TSC complex and Rheb to
regulation of muscle protein synthesis and size.
mTOR AND AMINO ACID AVAILABILITY
In addition to growth factors, mTOR is also known to be
regulated by the availability of amino acids (33, 46, 63, 68, 88).
In mammalian cells, amino acid deprivation leads to decreased
mTOR signaling and to decreased rates of protein synthesis,
effects that are rapidly reversed by readdition of amino acids
(30, 46). Among the amino acids, changes in leucine levels
alone are sufficient to regulate the phosphorylation state and
activity of the mTOR pathway (46, 69). Several studies in
rodents and human have shown that administration/ingestion of
essential amino acids (specifically leucine) leads to increased/
enhanced protein synthesis in skeletal muscle primarily through
activation of mTOR signaling (5, 24, 25, 32, 102). Currently, it is
widely accepted that amino acid availability affects mTOR signaling and protein synthesis rate; however, how amino acids
regulate the mTOR signaling pathway remains poorly understood.
For instance, it has been proposed that amino acids activate
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of cell cycle progression, differentiation, survival, and cell
growth [see Frost and Lang (31) for a more comprehensive
review on this topic]. Serine/threonine kinase Akt/PKB is a
well-established target of PI3K, and Akt/PKB phosphorylation
of glycogen synthase kinase 3 (GSK-3) leads to its inhibition
and an increase in global protein synthesis through increase in
the activity of eukaryotic initiation factor 2B (eIF2B; Ref.
106). Additionally Akt/PKB is a known upstream regulator of
mTOR signaling through regulation of the tuberous sclerosis
complex (TSC; Refs. 20, 58, 70, 79). The TSC protein complex
is a heterodimer of TSC1 and TSC2 and functions as a negative
regulator of mTOR activity. Cells null for TSC1 or TSC2, cells
depleted of TSC1 or TSC2 by RNA interference, and human
and mouse tissues deficient in TSC1 or TSC2, all have high
mTOR activity (33, 43, 58, 79). Together with its partner
TSC1, TSC2 functions as a guanosine triphosphate (GTP)ase
activating protein (GAP) for a small G protein named Ras
homolog enriched in brain (Rheb). It has been reported that
Akt/PKB directly phosphorylates TSC2 on multiple residues
(at least two sites, Ser939 and Thr1462; Refs. 55, 58, 70). This
phosphorylation of TSC2 by Akt/PKB is thought to inhibit its
GAP activity, allowing Rheb to accumulate in its active GTPbound form. GTP-bound Rheb strongly stimulates mTOR
activity, thus TSC2 functions as a negative regulator of mTOR
through increasing the intrinsic rate of GTP hydrolysis to GDP
on Rheb (34, 57, 60, 92). This leads to the well-established
growth factor associated signaling cascade through PI3K-Akt/
PKB-TSC1/2-Rheb-mTOR seen in muscle as well as other cell
types.
To date there have been very few studies that have incorporated analysis of TSC1/TSC2 or Rheb in the regulation of
protein synthesis during skeletal muscle growth/hypertrophy.
Consistent with the role of TSC complex as a negative regulator of muscle growth Wan et al. (104) reported that overexpression of human TSC1 in mouse skeletal muscle leads to
20% reduction of muscle mass and decreased fiber cross-
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mTOR REGULATION IN SKELETAL MUSCLE
MECHANOTRANSDUCTION OF mTOR SIGNALING
Work by Bodine et al. (11) established that mechanical
overload-induced signaling through mTOR was necessary for
skeletal muscle hypertrophy. Since then, many studies have
confirmed the association between mechanical loading and
activation of mTOR signaling in mammalian muscle. However, there is still very little known about the actual biochemical events that link the mechanical loading of a muscle/muscle
fiber to mTOR signaling. Ex vivo muscle stretch and in vitro
muscle cell stretch models of mechanical loading have defined
that 1) passive mechanical loading is sufficient to activate
mTOR signaling in skeletal muscle, 2) stretch-induced activation of mTOR occurs in a PI3K-independent manner, and
3) mechanical stretch can activate mTOR in the absence of
amino acids or growth factors (49, 50, 54). Our lab has found
that treatment of the myotubes with cytochalasin D to disrupt
the microfilament system (49) will block stretch-induced signaling to mTOR even though insulin activation of mTOR was
still intact. These results suggest that there is a cytoskeletal
requirement for communication of signaling pathway from
mechanical stretch to mTOR. Other intracellular targets of
stretch include phospholipase D1 (PLD1) and the lipid second
messenger phosphatidic acid (PA) as the mediators of stretchinduced mTOR signaling in skeletal muscle (51). The PLD1
pathway has been proposed to contribute to the activation of
mTOR through generating PA from the hydrolysis of phosphatidylcholine. PA binds specifically to the FRB domain of
the mTOR in a manner competitive with inhibitor rapamycin/
FKBP12 complex (28, 29). Recently, studies from Dr. Y.
Chen’s laboratory (91) identified that PLD1 is required for
Rheb activation of mTOR signaling, and their experiments
place PLD1 downstream of Rheb and upstream of mTOR.
Thus mechanical loading/stretch clearly acts independently of
amino acids and growth factors to activate mTOR signaling in
skeletal muscle. We believe that this mechanical pathway
likely acts synergistically with changes in amino acid uptake
J Appl Physiol • VOL
and growth factor availability to contribute to the prolonged
activation of mTOR signaling following high resistance contractions/mechanical overload.
CELLULAR ENERGY STATUS AND mTOR ACTIVITY
In addition to the availability of growth factors and amino
acids, the rate of protein synthesis is regulated by the cellular
energy status in muscle and non-muscle cells (13, 81). It has
been shown that glucose deprivation, through use of a nonhydrolyzable glucose analog (2-deoxyglucose), results in decreased mTOR signaling (21). It is currently suggested that
mTOR functions as a sensor of cellular energy state through
input from the AMP-activated protein kinase (AMPK) pathway
(60). AMPK is well known as a sensor of cellular energy
status, which is regulated by changes in the cellular levels of
AMP-to-ATP ratio (62). Inoki et al. (60) identified that, under
low cellular energy conditions, activated AMPK phosphorylates TSC2 on Thr1227 and Ser1345 residues (these residues
correspond to Thr1271 and Ser1387, respectively, in human
TSC2) and enhances its inhibitory function leading to decreased
mTOR activity. This research group has also reported that
AMPK-dependent phosphorylation of TSC2 on Ser1387 primes
TSC2 for further phosphorylation by GSK-3 on multiple residues. This series of phosphorylation steps leads to subsequent
inhibition of mTOR activity under energy-deprived conditions
(59). Additionally, a recent study by Gwinn et al. (45) reported that
AMPK can directly phosphorylate the mTOR binding partner
Raptor on two well-conserved serine residues (Ser722/Ser792),
and Raptor phosphorylation is required to inhibit mTOR activity through cellular energy stress-induced AMPK activation.
Consistent with these observations, it was demonstrated that
activation of AMPK, by treatment with 5-aminoimidazole-4-carboxamide-1-␤-D-ribonucleoside (AICAR), results in decreased
protein synthesis and a repression of mTOR-mediated signaling in skeletal muscle in both in vitro and in vivo experimental
models (12, 82, 107). Deshmukh et al. (22) reported that
preincubation with AICAR completely inhibited insulin-induced activation of mTOR signaling using an ex vivo organ
bath system. Thomson et al. (93) also reported that AICAR
treatment inhibited mTOR activation, which is induced by
high-frequency electrical stimulation of rat EDL muscle. Finally Thomason and Gordon (94) found a correlation between
increased phosphorylation of AMPK and reduced muscle hypertrophy in aging rats.
These studies indicate that activation of AMPK in skeletal
muscle will contribute to diminished protein synthesis through
inhibiting mTOR signaling. However, it is still controversial
whether an AMPK-dependent regulatory mechanism plays an
active role in exercise/contraction-induced skeletal muscle
growth responses. To address the potential role of AMPK in
muscle growth, McGee et al. (71) used the compensatory
hypertrophy model with mice lacking LKB1, the primary
upstream kinase for AMPK. The hypothesis for this study was
that decreased phosphorylation of AMPK, via loss of LKB1,
would enhance mTOR signaling and lead to a greater degree of
muscle hypertrophy in response to functional overload. To
their surprise, loss of LKB1 did not alter the growth of skeletal
muscle after 7 or 28 days of functional overload. Normal
hypertrophic responses were accompanied in skeletal muscle
of LKB1⫺/⫺ mice compared with the wild-type strain. How-
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mTOR in both a TSC1/TSC2-dependent (33) and TSC1/TSC2independent (88) manner. Some studies suggest that Rheb plays
an essential role in regulation of the mTOR activity in response to
amino acids (57) and that nutrient deprivation may decrease Rheb
binding to mTOR (68). However, other work implies that Rheb
may not be involved in nutrient-induced mTOR signaling, but
rather that nutrient poor conditions lead to alterations in the
proteins associated in the mTOR complex and this results in
decreased activity (63). Recently, a class III PI3K, hVps34, has
been implicated in the amino acid-induced activation of mTOR
signaling and this is independent of Akt/PKB-TSC-Rheb pathway
(15, 76). In addition, two research groups [Kim et al. (64) and
Sancak et al. (87)] reported that a heterodimeric complex of the
Rag proteins, a family of four related small GTPases, plays a
fundamental role in amino acid-induced regulation of mTOR/
TORC1 activity both in Drosophila and mammalian cells. It is
still unclear, however, what the relationship is between hVps34
and the Rag proteins in activating mTOR/TORC1 in response to
amino acids. The lack of consensus in the understanding of the
mechanisms by which amino acids regulate mTOR suggests that
other molecules, not yet identified, are involved in the signaling
and/or the mechanisms for signaling might be varied among
different cell types.
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mTOR REGULATION IN SKELETAL MUSCLE
ever, these authors found that while ␣2-AMPK activity was
reduced in the muscles of these mice, ␣1-AMPK was still
activated following overload in both the LKB1⫺/⫺ mice as
well as the wild-type mice. Thus the conclusion was that
␣2-AMPK is likely not an important molecule in the regulation
of mechanical load signaling to mTOR and growth.
STRESS RESPONSE GENES REDD1/REDD2 AND
mTOR SIGNALING
experiments that will consider balancing both the positive and
negative inputs to mTOR signaling in skeletal muscle.
GRANTS
This work was supported by National Institutes of Health AR-045617 to K. A.
Esser and American Heart Association Postdoctoral Fellowship 0825668D to M.
Miyazaki.
REFERENCES
SUMMARY
In summary, there is a long history of research in understanding the contribution of mechanical loading/resistance exercise to regulation of protein synthesis in skeletal muscle and
growth. The goal of this short review was to provide a general
overview linking what is currently known using well-established animal models and cell culture models of mechanical
loading and hypertrophy with regulation of mTOR, a key
kinase involved in protein synthesis and growth. One of the
unique features seen across all models of skeletal muscle
hypertrophy in humans and rodents is that rates of protein
synthesis and signaling through mTOR stay elevated for hours
to days after one bout of high-resistance contractions. We
propose in this review that the prolonged activation of mTOR
signaling, and thus rates of protein synthesis, is the cumulative
result of synergism among several independent positive signals
including mechanical loading, amino acids, and growth factors.
We also suggest that resistance exercise/mechanical loading
can act to dampen the inhibitory contributors to mTOR signaling via downregulation of the TSC complex and REDD1/
REDD2 molecules. Thus to understand the critical molecular
and cellular steps involved in resistance exercise-induced regulation of protein synthesis will require carefully designed
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Another negative regulator of mTOR activity are two factors
that were originally identified from a genetic screen for negative regulators of the Drosophila TOR pathway (83). The
mammalian orthologs are called REgulated in Development
and DNA damage responses 1 (REDD1) and REDD2 (also
called RTP801/DDIT4 and RTP801L/DDIT4L, respectively).
REDD1 is ubiquitously expressed in all cell types while expression of REDD2 is significantly enriched in human and
mouse skeletal muscle (http://symatlas.gnf.org/SymAtlas/).
Cros et al. (19) identified REDD2 (also named SMHS1) as a
highly upregulated gene in soleus muscle undergoing atrophy
following 14 days of hindlimb unloading (78). Biochemical
studies of both REDD1 and REDD2 found that they inhibit
mTOR kinase activity in non-muscle and muscle cells downstream of Akt/PKB but upstream of TSC2 (14, 18, 89, 105). In
skeletal muscle, REDD1 has been shown to inhibit mTOR
signaling and protein synthesis in response to dexamethasone
and alcohol intoxication (67, 105). In addition, Kimball et al.
(65) found that rapid degradation of REDD1 in muscle was
associated with enhanced mTOR signaling. Recent studies in
human skeletal muscle have also suggested that expression of
REDD1 and REDD2 plays a role in regulating mTOR activity
and protein synthesis (26, 27). These observations suggest the
possibility that REDD1 and REDD2 are stress responsive
negative regulators of mTOR signaling with implications for
controlling skeletal muscle size.
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