J Appl Physiol 110: 561–568, 2011.

First published November 11, 2010; doi:10.1152/japplphysiol.00941.2010. Review

HIGHLIGHTED TOPIC Signals Mediating Skeletal Muscle Remodeling by Activity

Signals mediating skeletal muscle remodeling by resistance exercise:

PI3-kinase independent activation of mTORC1
Andrew Philp,1 D. Lee Hamilton,2 and Keith Baar1
1
Department of Neurobiology, Physiology, and Behavior, University of California–Davis, Davis, California;
and 2Biomedical Research Institute, University of Dundee, Dundee, Scotland
Submitted 16 August 2010; accepted in final form 5 November 2010

Philp A, Hamilton DL, Baar K. Signals mediating skeletal muscle remod-

eling by resistance exercise: PI3-kinase independent activation of mTORC1. J
Appl Physiol 110: 561–568, 2011. First published November 11, 2010;
doi:10.1152/japplphysiol.00941.2010.—For over 10 years, we have known that
the activation of the mammalian target of rapamycin complex 1 (mTORC1) has
correlated with the increase in skeletal muscle size and strength that occurs
following resistance exercise. Initial cell culture and rodent models of muscle
growth demonstrated that the activation of mTORC1 is common to hypertrophy
induced by growth factors and increased loading. The further observation that high
loads increased the local production of growth factors led to the paradigm that
resistance exercise stimulates the autocrine production of factors that act on
membrane receptors to activate mTORC1, and this results in skeletal muscle
hypertrophy. Over the last few years, there has been a paradigm shift. From both
human and rodent studies, it has become clear that the phenotypic and molecular
responses to resistance exercise occur in a growth factor-independent manner.
Although the mechanism of load-induced mTORC1 activation remains to be
determined, it is clear that it does not require classical growth factor signaling.
mammalian target of rapamycin complex 1

SINCE THE ELEGANT EXPERIMENTS by Wong and Booth (83– 85) in
the late 1980s, we have known that the load across a muscle is
the primary determinant of skeletal muscle hypertrophy (for
review, see Ref. 3). However, how the load across a muscle is
transduced into an increase in the rate of protein synthesis and
the accretion of contractile protein has yet to be fully deter-
mined. The first molecular marker of the increase in muscle
mass and strength following resistance exercise was the phos-
phorylation and activation of the 70-kDa ribosomal S6 protein
kinase (S6K1; Refs. 4, 51, 73). Subsequent work demonstrated
that S6K1 was under the control of the mammalian target of
rapamycin (mTOR) complex 1 (mTORC1) and that the specific
mTORC1 inhibitor, rapamycin, could directly block muscle
growth (11). These initial studies have since been supported by
transgenic models of mTORC1 inactivation (59) and dissoci-
ation (9) and global knockout of S6K1 (66). Collectively, these
studies implicate mTORC1 and S6K1 as principal mediators of
muscle growth in skeletal muscle.
The original observation that S6K1 correlated with muscle
growth was striking since S6K1 had formally been identified as
a mitogen (or growth factor) activated protein kinase (42, 55,
58) whose activity was correlated with the phosphorylation of
ribosomal proteins and the mitogen-induced increase in protein
synthesis (74). Since increased load across a muscle increased
the rate of protein synthesis (16, 50, 83, 84) and growth factors
like insulin-like growth factor (IGF)-1 were known to induce
muscle hypertrophy (18), the natural hypothesis was that mus-
cle hypertrophy in the adult was the result of an increase in
mitogen signaling following resistance exercise. In support of
this hypothesis, treating myotubes with IGF-1 in vitro resulted
in the activation of S6K1 and an increase in the size of the
myotubes (60); following loading there was an increase in the
expression of IGF-1 mRNA in muscle that occurred even in
the absence of growth hormone (23); and stretching myotubes
in vitro resulted in the release of a factor into the media that
was able to activate S6K1 (5). So the growth factor paradigm
was set: 1) resistance exercise increased the autocrine release
of IGF-1; 2) IGF-1 bound to the IGF-1 receptor on the cell
surface and activated S6K1 via the canonical growth factor
pathway; 3) activation of S6K1 led to an increase in protein
synthesis; and 4) when repeated at a sufficient frequency, this
autocrine signaling response led to an increase in muscle mass
and strength (Fig. 1).
DECONSTRUCTING THE PARADIGM: GROWTH FACTOR-
INDEPENDENT ACTIVATION OF S6K1

Address for reprint requests and other correspondence: K. Baar, 1 Shields Over the last few years, pharmacological, genetic, and trans-
Ave., 174 Briggs Hall, Univ. of California, Davis, CA 95616 (e-mail: genic approaches have been employed by several groups to
kbaar@ucdavis.edu). systematically manipulate the IGF1-PI-3 kinase-PKB pathway
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Review
562

Fig. 1. Canonical growth factor signaling path-

way from insulin/IGF1 to mTORC1 and pro-
tein synthesis. Growth factor binding to the
receptor results in auto tyrosine phosphoryla-
tion and recruitment of the insulin receptor
substrates (IRS). IRS relocalization and phos-
phorylation recruit phosphoinositol-3 kinase
(p85 and p110/PI3K) to the membrane result-
ing in the phosphorylation of PI4,5P2 into
PI3,4,5P3(PIP3). PIP3 recruits protein kinase B
(PKB) and phosphoinositol-dependent kinase
(PDK)1 to the membrane resulting in activation
of PKB. PKB phosphorylates and inactivates
the GTPase-activating tuberosclerosis complex
(TSC1/2). Inactivation of TSC results in the
activation of the ras homologous protein en-
riched in brain (Rheb) and mTORC1 (mTOR,
raptor, and G␤L). mTORC1 phosphorylates its
primary downstream targets of the eukaryotic
initiation factor 4E binding protein (4EBP) and
the 70KDa ribosomal S6 protein kinase (S6K1),
resulting in an increase in protein synthesis.

and determine its importance in load-induced muscle growth.
The first suggestion that the increase in S6K1 activation fol-
lowing loading could occur independent of canonical growth
factor signaling came in 2004 when Hornberger et al. (40)
showed that ex vivo stretch of isolated extensor digitorum
longus muscles in the presence of the PI3-kinase inhibitor
wortmannin did not prevent the stretch-induced activation in
S6K1. In these experiments, insulin activation of S6K1 was
prevented by both wortmannin (PI-3 kinase inhibitor) and
rapamycin (an inhibitor of mTORC1), indicating that insulin
activated S6K1 by the canonical growth factor ¡ PI-3 kinase
¡ mTORC1 ¡ S6K1 pathway. However, stretch activation of
S6K1 occurred in a rapamycin-sensitive, wortmannin-indepen-
dent mechanism, demonstrating for the first time that PI-3
kinase was not required for stretch-induced activation of
mTORC1. In support of this hypothesis, protein kinase B/Akt,
the molecular link between PI-3 kinase and mTORC1, was not
required for S6K1 activation by stretch (40). However, it
should be noted that both wortmannin and rapamycin blocked
the stretch-activated increase in protein synthesis, suggesting
that PI-3 kinase was, in the least, permissive for the actions of
stretch on protein synthesis.
The next major blow to the growth factor paradigm came in
2008 from the laboratory of Espen Spangenburg (67). Using a
mouse with skeletal muscle that harbored an inactivating
knockin mutation in the IGF receptor (MKR) that prevented
receptor activation by insulin or IGF-1, Spangenburg and
colleagues (67) showed that, in the absence of IGF signaling,
load-induced muscle hypertrophy was identical to that of
wild-type mice, even though muscles from the MKR mice did
not grow as large developmentally. At 8 wk of age, the muscles
of the MKR mice were ⬃30% smaller than wild-type mice,
and neither insulin nor IGF-1 could activate PKB/Akt, showing
that IGF-1 and PI-3 kinase signaling is required for develop-
mental muscle growth. However, following 7 or 35 days of
mechanical overload, both the wild-type and the MKR mice
showed an increase in muscle mass of ⬃50 and 90%, respec-
tively. Furthermore, the phosphorylation of both PKB and
S6K1 was completely normal in the MKR mice in response to
overload.
However, two points should be made regarding the MKR
mouse model. First, it should be noted that a follow-up study
by the same group (82) showed that, in response to an acute
bout of resistance exercise, the MKR mice did show a delayed
and diminished phosphorylation of S6K1 in response to resis-
tance exercise, suggesting that input from PI-3 kinase maybe
required for full activation of mTORC1. Second, Heron-Mil-
havet and colleagues (38) recently reported that the MKR mice
demonstrate impaired muscle regeneration and myoblast dif-
ferentiation following injury. Furthermore, the authors ob-
served an increase in progenitor cell number in the MKR mice
and speculated that the normal response to overload hypertro-
phy reported by Spagenburg and colleagues may be through
compensatory hyperplasia (increased activation and prolifera-
tion of progenitor cells), as has previously been reported (27).
However, it is not clear how this would occur if myoblast
differentiation were impaired. In fact, the inability to regener-
ate and a decrease in myoblast differentiation suggests a
decrease in satellite cell activation and fusion in the MKR
mice, bringing into question the need for these cells for
hypertrophy in the mouse.
Using another genetic model (electroporation of DNA into
adult muscle), Goodman et al. (33) have shown that activation
of PI-3 kinase is not required for mTORC1-induced skeletal

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muscle hypertrophy. In these experiments, the small G-protein
activator of mTORC1, Rheb (ras homologous protein enriched
in brain), was overexpressed either in vitro or in vivo to
increase mTORC1 activity in a PI-3 kinase-independent fash-
ion. The authors were then able to demonstrate that augment-
ing Rheb levels increased cap-dependent translation and re-
sulted in a 64% increase in the cross-sectional area of muscle
fibers. Even though Goodman et al. (32) did not demonstrate
Rheb association with mTORC1 following load-induced hy-
pertrophy, their data can be interpreted to show that PI-3
kinase-independent skeletal muscle hypertrophy is genetically
possible in vivo.
It is one thing to demonstrate that experimental models can
be genetically created where adult muscle growth can occur in
a growth factor-independent manner; it is another thing entirely
to show this in humans. West et al. (80) have done just that by
taking advantage of the fact that resistance exercise using a
large muscle mass increases circulating levels of anabolic
hormones (1). Using heavy resistance exercise with the legs,
West and colleagues were able to create a high hormone state.
The high hormone state was characterized by a 5-fold increase
in total testosterone, a 3-fold increase in free testosterone, and
a 10-fold increase in both growth hormone and IGF-1. The
authors then used a unilateral resistance exercise program in
the arms where one arm performed resistance exercise imme-
diately before heavy lifting with the legs (therefore in a high
hormone state), whereas the other arm was exercised on a
separate day without concomitant exercise of the legs (a low
hormone state). Despite the huge differences in circulating
hormone levels subsequent to each bout of exercise, there was
no difference in either the increase in muscle fiber size or
overall strength in the arms following 15 wk of training.
Consistent with the absence of a difference in muscle strength
or fiber size, they have also demonstrated that mTORC1
signaling was not different between the high and low hormone
states (81). This work confirms earlier animal studies that
showed that neither hypothalamic nor pancreatic hormones
were required for load-induced skeletal muscle hypertrophy
(30, 31). However, the fact that circulating hormones are not
required for muscle hypertrophy does not preclude the possi-
bility that local production of IGF-1 or another growth factor
may play an important role in adult skeletal muscle hypertro-
phy.
Given the data from the Spangenburg and Hornberger lab-
oratories using transgenic approaches, growth factor-indepen-
dent hypertrophy is possible. However, whether this was due to
compensatory changes in the muscle and whether autocrine
signaling through tyrosine phosphorylation of the IGF-1 recep-
tor and the insulin receptor substrates (IRS) to PI-3 kinase
occurred normally remained an open question. We have re-
cently directly tested this hypothesis in rat and mouse skeletal
muscle in response to high-frequency electrical stimulation
(37). In support of IGF-1-independent activation of mTORC1,
at no time following resistance exercise (from immediately
after to 48 h later) was there an increase in tyrosine phosphor-
ylation of the IGF-1 receptor. Furthermore, we observed a
decrease in signaling through IRS1/2 to PI-3 kinase. In sharp
contrast to insulin, p85 associated with either IRS1 or IRS2
decreased in the first 3 h after the resistance exercise before
returning to control levels (37). To determine whether this was
a measurement error or possibly that PI-3 kinase was activated
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563
in an IRS1/2-independent manner, we generated mice with
muscles devoid of the phosphoinositol phosphatase PTEN. We
hypothesized that if PI-3 kinase was important in the activation
of mTORC1 following loading, the PTEN knockout mice
would show greater accumulation of PI(3,4,5)P3 and therefore
greater PKB/mTORC1 activity and muscle hypertrophy. In
contrast to this hypothesis, neither the phosphorylation of
S6K1 following resistance exercise nor the increase in muscle
mass following overload was different between the wild-type
and PTEN knockout mice.
The activation of mTORC1 in a PI-3 kinase-independent
manner is consistent with both the time course of PKB and
S6K1 activation and the variability observed in PKB activation
following resistance exercise (Fig. 2). We and others (54) have
shown that following resistance exercise the activation of
S6K1 precedes or occurs concomitant with that of PKB and, in
humans, the activation of PKB following resistance exercise is
more dependent on the feeding state rather than the intensity of
the exercise session (22). Since most animal studies occur in
the fed state, whereas the feeding state is far more controlled in
human studies, these findings are completely consistent with
PKB being activated by an increase in nutrients resulting from
the increase in blood flow during, or immediately following,
exercise and not the exercise bout or the autocrine release of
growth factors.
A NEW PARADIGM: MECHANOSENSING DRIVES
LOAD-INDUCED SKELETAL MUSCLE HYPERTROPHY
Taken together, the above data support a new paradigm
where mTORC1 is activated in a PI-3 kinase/PKB-independent
manner. This shift in paradigm parallels research into the
activation of mTORC1 by amino acids. Like resistance exer-
cise, amino acids activate mTORC1 in a PI-3 kinase/PKB-
independent manner. Instead of working through the PI-3
kinase/PKB pathway, amino acids activate mTORC1 by alter-
ing its subcellular location (45, 46, 61, 62). In the absence of
amino acids, mTORC1 is diffuse throughout the cell. When
amino acids are added back, mTORC1 is shuttled to the
lysosomal membrane through its interaction with the Rag
family of small G-proteins and the Ragulator, a protein scaf-
fold found on the lysosomal membrane (45, 61, 62). Once at
the lysosome, mTORC1 can interact with Rheb. The interac-
tion with Rheb increases the basal level of mTORC1 activity
and permits the activation of mTORC1 by growth factors and
other stimuli (61). This model fits very well with what we
know about skeletal muscle hypertrophy: 1) the basal level of
mTORC1 activity (as determined by S6K1 phosphorylation) is
extremely low; 2) the addition of amino acids increases
mTORC1 activity and protein synthesis (7, 12, 13, 20); 3) the
ability of amino acids and loading to increase protein synthesis
is dependent on a permissive level of hormonal activity (8, 26,
40); and 4) growth factors and resistance exercise can acti-
vate mTORC1 and increase protein synthesis more effi-
ciently in the presence of amino acids (57, 72, 75, 76).
Interestingly, we have shown that resistance exercise in-
creases the activity of the vesicular trafficking protein
Vps34 (51). This might improve the trafficking of mTORC1
to the lysosome and permit the prolonged activation of
mTORC1 following resistance exercise. However, whether
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564
Fig. 2. The phosphorylation of S6K1 precedes that of PKB in rodent muscle
following resistance exercise. Western blots showing the phosphorylation of
PKB (A) and S6K1 (C) following resistance exercise. Notice first that S6K1
phosphorylation occurs before that of PKB in post absorptive rats following 10
sets of 6 contractions induced by high-frequency electrical stimulation. Sec-
ond, notice that PKB phosphorylation is elevated only transiently (at 30 min),
whereas S6K1 remains phosphorylated for at least 18 h. Last, notice the
magnitude of the activation. PKB phosphorylation increases 3-fold, whereas
S6K1 phosphorylation increases ⬃80-fold (36).
resistance exercise increases mTORC1 association with Rheb
at the lysosome has yet to be determined.
Amino acid signaling through the RagGTPase proteins to
mTORC1 provides a viable signaling mechanism; namely that
the GTP binding state of the Rag heterodimer is altered in the
presence of amino acids (45, 61, 62). However, it is unclear
how a change in the load on a muscle would produce a PI-3
kinase-independent signal to mTORC1. The obvious answer is
that there is a mechanosensor that can independently activate
mTORC1. However, the identity of such a sensor remains
elusive. The ideal position for a mechanosensor is within a
region that connects the internal architecture of the cell to the
extracellular matrix or to other cells (41). A number of protein
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complexes serve this purpose in muscle including the dystro-
phin-associated glycoprotein complex, integrin-associated cos-
tameric complex, and cell-cell adherins junctions. The role of
some of these protein complexes in mechanosensing has been
studied in the heart with some interesting results. In the heart,
the costameres appear to be the primary mechanical sensor.
␤-Integrins (44, 65), the integrin-linked kinase (ILK) (6),
melusin (14, 21), the muscle LIM domain protein (47), and
PKB all are found in costameres and all play an important role
in mechanosensing and cardiac hypertrophy. Of specific inter-
est is ILK. ILK is primarily a scaffolding protein but may still
harbor some kinase activity. The primary role of ILK in
hypertrophy is due to its ability to interact and bring together
␤-integrins, PKB, and the rapamycin-insensitive companion of
mTOR (rictor). Rictor coordinates the phosphorylation of PKB
at Thr473 as part of the other known mTOR complex
(mTORC2). The activation of PKB can lead to muscle hyper-
trophy in both the heart and skeletal muscle (11), suggesting
that ILK may coordinate the conversion of the mechanical
stimulus from the ␤-integrins into the chemical signal of PKB
phosphorylation. However, as discussed above, PKB␣/Akt1 is
not required for the activation of mTORC1 in response to
stretch. This means that either other isoforms can compensate
for the loss of PKB␣/Akt1 in muscle or the ␤-integrin/ILK/
PKB/mTORC1 pathway is not the mechanosensor in skeletal
muscle.
Another member of costameres and adherins junctions is
focal adhesion kinase (FAK) (15). Work by Fluck et al. (28)
demonstrated that the amount and activity of FAK increase
within 24 –36 h of the onset of stretch in the chicken ALD and
in the rat soleus after overload. Furthermore, the degree of
FAK expression and activity in muscles is related to their
loading (34). For instance, the postural soleus muscle has
greater expression and tyrosine phosphorylation of FAK than
the gastrocnemius or plantaris (34). Moreover, unloading re-
duces the phosphorylation of FAK in the soleus and the
concentration of FAK in the gastrocnemius and plantaris (34).
This suggests that load may be sensed through FAK. However,
unlike ILK, it is unclear what the downstream targets of FAK
may be involved in this process; additionally, it has yet to be
determined whether FAK is activated by acute resistance
exercise with a time course consistent with it being proximal to
mTORC1.
Calcium has also been proposed as a mechanosensor. Gu-
haray and Sachs (35) first identified stretch-activated ion chan-
nels that could be blocked by the antibiotic streptomycin and
the cation gadolinium. Spangenburg and McBride (68) have
shown that treating animals with streptomycin or gadolinium
before a bout of resistance exercise can decrease S6K1 activa-
tion without impacting muscle function, suggesting that these
channels may be important in mechanosensing. Further support
for this theory comes from the fact that increasing intracellular
calcium in muscle cells using the calcium ionophore A23187
enhances both protein synthesis and degradation rates (43)
much like resistance exercise. However, stretch in combination
with A23187 enhances protein synthesis further than treatment
with A23187 alone (43). This means that, although calcium
influx may play a role in mechanosensing, it is not the only
stretch sensor in muscle.
Goldberg and Goodman (32) were the first to observe that
amino acid transport into loaded muscles was increased in both

normal and hyposectamized rats. An increase in amino acid
uptake, specifically the branched chain amino acids, is also
seen 3 h after resistance exercise in humans (10) and 90 min
after resistance exercise in rats (51). As discussed above,
amino acids, specifically leucine, are known to activate
mTORC1 via the RagGTPases (45, 61, 62) and increase
muscle protein synthesis, suggesting that amino acid influx
may function as a mechanosensor in skeletal muscle. In fact,
when muscle cells are stretched in vitro, the increase in amino
acid uptake is required for stretch-induced activation of protein
synthesis (77). Since the permeability of muscle to amino acids
increases following resistance exercise and amino acids in-
crease mTORC1 activity and protein synthesis, it is not sur-
prising that protein supplementation in association with resis-
tance exercise has a synergistic effect on protein synthesis rates
and muscle hypertrophy (25, 48, 75). However, the influx of
amino acids is not seen immediately after resistance exercise
and rapidly returns to normal (3 h in the rat), even though
mTORC1 activity remains high for at least another 15 h (51).
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565
In the absence of external amino acids, protein degradation
may play an important role in supplying amino acids for the
activation of mTORC1 and protein synthesis (63, 64). Early
studies in fasting humans demonstrated a direct association
between protein synthesis and degradation following resistance
exercise (56). However, when essential amino acids are sup-
plied, the increase in degradation is attenuated (75), suggesting
that degradation serves to increase internal amino acids, pro-
vide a source of essential amino acids for de novo synthesis,
and possibly activate mTORC1.
Hornberger and his colleagues have suggested that the phos-
pholipid cleaving enzyme phospholipase D (PLD) could serve
as a mechanoreceptor. One of the products of PLD, the second
messenger phosphatidic acid (PA), increases in response to
15–90 min of mechanical stretch (39) or within 2 min follow-
ing the start of electrical stimulation (17). Hornberger and his
group (39, 54) have used two chemically distinct inhibitors of
PLD to demonstrate that blocking PLD prevents the production
of PA in response to stretch and the mechanical activation of

Fig. 3. Mechanical activation of mTORC1. In this model, the initiating signal for mTORC1 activation goes through a stretch-activated calcium channel, integrins
[␣/␤ and integrin linked kinase (ILK)], and/or amino acids. These signals activate Rheb and induce the RagGTPase-dependent recruitment of mTORC1 to the
lysosome. With mTORC1 at the lysosome, Rheb activates mTORC1 possibly through the recruitment of phospholipase D (increasing PA locally). Once active,
mTORC1 phosphorylates its downstream targets 4EBP and S6K1, upregulates miR-1 resulting in an increase in follistatin and myostatin inhibition, and increases
amino acid transporters possibly through the myc protooncogene. S6K1 in turn phosphorylates upstream binding factor (UBF) and elongation factor (EF) 2
kinase, resulting in a decrease in eEF2 phosphorylation.

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Review
566
mTORC1 (Fig. 3). Furthermore, the same group has shown
that the increase in PA with in vivo contractions only occurs in
muscles that will undergo hypertrophy (54). These data suggest
that PA is important in the activation of mTORC1 by mechan-
ical loading. However, whether PLD activation is the mechan-
ical sensor or simply a marker of an upstream event has yet to
be determined. RNA interference experiments have revealed
that the mTORC1 activator Rheb binds to, and activates, PLD
in a GTP-dependent manner (70). Knockdown of PLD pre-
vents Rheb-induced activation of mTORC1, whereas knock-
down of Rheb decreases the activation of PLD in response to
serum (70). In contrast, Rheb overexpression activates PLD in
serum-starved cells. Together, these data suggest that activa-
tion of Rheb recruits PLD to mTORC1 and enhances the local
production of phosphatidic acid, resulting in the activation of
mTORC1. Therefore, the activation of PLD by mechanical
loading may simply reflect the upstream activation of Rheb and
not that PLD is a mechanosensor per se.
CONCLUSIONS
Even though we have focused on the role of mTORC1 and
S6K1 in the development of skeletal muscle hypertrophy, this
is not the only mediator of adult muscle growth. Myostatin (78,
79), notch (19, 53), and microRNAs (24, 52) also play an
important role in the development of muscle hypertrophy.
However, whether these are distinct pathways or part of a
coordinated system has yet to be determined. For instance,
mTORC1 can regulate the production of miR-1, resulting in an
increase in the endogenous inhibitor of myostatin, follistatin
decreasing myostatin activity (71). In turn, myostatin can
inhibit the activation of mTORC1 (2, 78). Together, these
effects would produce a positive feedback loop following
resistance exercise where the activation of mTORC1 would
decrease myostatin signaling, the decrease in myostatin would
increase mTORC1 activity, and the cycle would repeat.
It is likely that more than one factor is responsible for
growth signaling in response to resistance exercise. It is pos-
sible that one sensor starts the cycle and the others function to
maintain mTORC1 activity at various times after resistance
exercise. Since the ability to increase protein synthesis and
accrue muscle is an important and evolutionarily conserved
process, it would not be surprising if significant redundancy
existed, making it difficult to dissect out the hierarchy of these
signals. It is important to make clear that for the sake of this
concise review series we decided to discuss factors involved in
muscle hypertrophy following mechanical loading. As noted in
the recent Point-Counterpoint series in this Journal (29, 69),
IGF-1 has important functions in development, the remodeling
of skeletal muscle, the extracellular matrix, and the activation
of progenitor cells. Certainly, in humans it is likely that many
molecular signals are required to maintain or increase muscle
mass. Therefore, future research, such as the innovative ap-
proach employed by West et al. (80), is needed to determine
whether murine models translate completely to humans. These
studies are extremely relevant because, with the growing el-
derly population and the anabolic resistance and muscle loss
that occurs with age (49), viable clinical options to rectify this
situation are desperately needed. These issues, as well as how
mTORC1 is activated and what mTORC1 does, should keep us
busy for years to come.
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DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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