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42
Background
Skeletal muscle mass is regulated by complex molecu-
lar systems that have only recently been determined 
(1). Mechanical overload induces skeletal muscle 
hypertrophy, but the molecular mechanisms are not 
fully understood (2).
The conversion of mechanical information into 
biochemical events is known as mechanotransduc-
tion and it seems to be the key mechanism in inducing 
muscle protein synthesis (3). Previous studies have (4,5) 
described that insulin like growth factor 1 (IGF-1) bind-
ing to its receptor, and the subsequent phosphorylation 
of phophatidyl inositol 3-kinase (PI3K) and protein 
kinase B (Akt) were considered necessary for hypertro-
phy process induced by mechanical overload, and that 
mammalian target of rapamycin complex 1 (mTORC1) 
was dependent to this signaling event. However, recent 
evidence has shown that mechanical signal transduction 
induces growth through a mechanism other than growth 
factor signaling (3,6–8). However, it is not clear whether 
this is the main mechanism that activates mTORC1 (9). 
Recently, it was reported that the phospholipid enzymes 
phospholipase D (PLD) and phosphatidic acid (PA) act 
as potential activators of mTORC1, but the mechanisms 
involved in this process are largely unexplored (10,11). 
Despite exciting findings, the key sensor involved in 
muscle hypertrophy in response to mechanical overload 
remains elusive. Based on the body of evidence presented 
herein, the purpose of this opinion paper is to highlight 
cellular and molecular mechanisms that control muscle 
mass, and to discuss how mTORC1 is activated in load-
induced skeletal muscle hypertrophy.
EXPERT OPINION
Mechanotransduction pathways in skeletal muscle 
hypertrophy
André Katayama Yamada1, Rozangela Verlengia2, and Carlos Roberto Bueno Junior3
1Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, São Carlos, São Paulo, Brasil, 
2Departamento de Educação Física, Faculdade de Ciências da Saúde, Universidade Metodista de Piracicaba, 
Piracicaba, São Paulo, Brasil, and 3Universidade de São Paulo, Instituto de Biociências, São Paulo, São Paulo, Brasil 
Abstract
In the last decade, molecular biology has contributed to define some of the cellular events that trigger skeletal 
muscle hypertrophy. Recent evidence shows that insulin like growth factor 1/phosphatidyl inositol 3-kinase/protein 
kinase B (IGF-1/PI3K/Akt) signaling is not the main pathway towards load-induced skeletal muscle hypertrophy. 
During load-induced skeletal muscle hypertrophy process, activation of mTORC1 does not require classical growth 
factor signaling. One potential mechanism that would activate mTORC1 is increased synthesis of phosphatidic acid 
(PA). Despite the huge progress in this field, it is still early to affirm which molecular event induces hypertrophy in 
response to mechanical overload. Until now, it seems that mTORC1 is the key regulator of load-induced skeletal 
muscle hypertrophy. On the other hand, how mTORC1 is activated by PA is unclear, and therefore these mechanisms 
have to be determined in the following years. The understanding of these molecular events may result in promising 
therapies for the treatment of muscle-wasting diseases. For now, the best approach is a good regime of resistance 
exercise training. The objective of this point-of-view paper is to highlight mechanotransduction events, with focus on 
the mechanisms of mTORC1 and PA activation, and the role of IGF-1 on hypertrophy process.
Keywords: Mammalian target of rapamycin complex 1, phosphatidic acid, cell signaling, skeletal muscle plasticity, 
mechanical overload
Address for Correspondence: Mr. André Katayama Yamada, Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos, 
Rodovia Washington Luís, Km 235, São Carlos, São Paulo, Brasil, CEP 13565-905. E-mail: yamadaak@gmail.com
(Received 26 September 2011; revised 26 October 2011; accepted 15 November 2011)
Journal of Receptors and Signal Transduction, 2012; 32(1): 42–44
© 2012 Informa Healthcare USA, Inc.
ISSN 1079-9893 print/ISSN 1532-4281 online
DOI: 10.3109/10799893.2011.641978
Journal of Receptors and Signal Transduction
2012
32
1
42
44
26 September 2011
26 October 2011
15 November 2011
1079-9893
1532-4281
© 2012 Informa Healthcare USA, Inc.
10.3109/10799893.2011.641978
LRST
641978
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mailto:yamadaak@gmail.com
http://informahealthcare.com/doi/abs/10.3109/10799893.2011.641978
Mechanotransduction and hypertrophy 43
© 2012 Informa Healthcare USA, Inc. 
mTORC1 and S6K1 drive hypertrophy
The protein mTORC1 is a serine/treonine kinase 
involved in a wide range of physiological processes, 
including adult muscle cell growth (12). This kinase 
is crucial in amplifying protein synthesis in response 
to mechanical overload (2). p70 Ribosomal protein 
S6 kinase 1 (S6K1), a downstream target of mTORC1, 
plays an important role in the translation of contractile 
proteins, and it correlates well with muscle hypertro-
phy. As such, it can be used as a marker for protein 
synthesis (13). This concept is based on a seminal work 
by Baar and Esser (13) in 1999, who showed for the 
first time that mechanical overload can increase S6K1 
phosphorylation levels, and that this increase is highly 
correlated with the hypertrophic phenotype (13). Two 
years later Bodine et al. (5) showed that S6K1 was under 
mTORC1 control and that a potent inhibitor of this 
pathway, rapamycin, blocked the increase in muscle 
mass (5). Other groups have reproduced these findings, 
showing that rapamycin blocks the muscle protein syn-
thesis related to mechanical overload (14,15). In gen-
eral, mTORC1 and S6K1 appear to function as potential 
anabolic markers of skeletal muscle hypertrophy in 
response to mechanical overload. The identification 
of other signaling components of mTORC1 may pave 
the way to the progress in muscle biology and future 
therapies.
The irrelevant growth factor
The signaling pathway IGF-1/PI3K/Akt is considered the 
key mediator of normal muscle development and one of 
the most studied molecular systems. Past investigation 
indicates that IGF-1 by binding to its receptor, for example, 
can promote fine biochemical events, and phosphorylate 
an enzyme known as PI3K, which in turn activates Akt 
kinase. The Akt activation results in activation of down-
stream kinase mTORC1 pathway, modulating muscle 
hypertrophy phenotype. The growth factor paradigm 
originated from a study (4) showed that IGF-1 treatment in 
vitro activated S6K1 and induced increase in myotube size. 
Thus, it was demonstrated that the expression of IGF-1 was 
also increased even without growth hormone stimulation; 
and that when mechanically stimulated, S6K1 remained 
activated (4). For many years the growth factor paradigm 
remained stable until 2004, when Hornberger’s lab showed 
that stretching the extensor digital longus (EDL) in the 
presence of IGF-1 inhibitor (wortmannin) did not prevent 
S6K1 activation mediated by stretching (3). This was the 
first evidence showing that mTORC1 activation could be 
triggered by a PI3K independent mechanism. However, 
administration of both rapamycin and wortmannin inhib-
ited protein synthesis, indicating that PI3K even having 
minor role on mechanical overload, has a limited thresh-
old of muscle mass maintenance (3).
The next remarkable landmark occurred in 2008 in a 
study (6) that used a skeletal muscle mouse model that 
harbored an inactivating knock-in mutation on IGF-1 
receptor (IGF-1R), where the IGF-1 system was inacti-
vated. It was demonstrated that in the absence of IGF-1 
signaling, the load-induced muscle hypertrophy was 
similar of that observed in wild-type mice. In 8 weeks 
of life, muscle of IGF-1R mutant mice(MKR) was 30% 
smaller than the wild-type littermates, showing that 
IGF-1 is important in muscle development (6). However, 
unexpectedly, during 7 and 35 days of overload, both 
the groups displayed increase in muscle mass, and the 
most striking finding was that MKR mice showed normal 
phosphorylation levels of S6K1 and Akt (6).
Other studies have found similar findings. Employing 
transgenic animals expressing several mutant mTORC1 
proteins, the authors observed that PI3K was not neces-
sary for hypertrophic mTORC1 event (7). It is important 
highlight that this study did not use mechanical overload, 
but provided strong insights of how genetic model can be 
used as a system, and also provided evidence that hyper-
trophy can be enhanced in vivo without PI3K (7).
A recent study (8) strengthened the previous findings 
showing that mTORC1 is activated following mechani-
cal overload independently on IGF-1/PI3K/Akt pathway 
in C57BL/6J mice. During 10 days of overload, hyper-
trophy, increase in RNA content and protein synthesis 
were observed. The authors monitored S6K1 and Akt 
phosphorylation in a transient fashion. Surprisingly, the 
group observed phosphorylation of S6K1 already in the 
first day, whereas Akt did not present alterations even 
after 3 days of overload (8). This study demonstrated that 
mitogen activated kinase/extracellular signal-regulated 
kinase (MEK/ERK) signaling can regulate mTORC1 
trough tuberous sclerosis protein 2 (TSC2) phosphoryla-
tion in serine 664 site. These findings clearly show that 
mTORC1 have an important role on muscle growth in 
vivo in the initial step of resistance exercise bout and 
in an IGF-1 independent manner (8). The ERK pathway 
now may enter in the forefront stage in muscle hypertro-
phy biology. The cross-talk between mTORC1 and ERK 
pathways will provide promising issues to be explored in 
coming years.
Phosphatidic acid: “new kid on the block”?
The knowledge that mTORC1 can be activated indepen-
dently of IGF-1 signaling in mechanical overload models, 
naturally leads one to imagine that some molecule might 
be activating mTORC1. This idea led Hornberger et al. (10) 
to make an important groundbreaking discovery where 
they elegantly provided strong evidence that mTORC1 
is being activated trough phospholipase enzyme PA10. 
Two inhibitors of PLD were used to inhibit PA synthesis 
in response to mTORC1 activated mechanical overload 
(10). However, there are some unanswered questions. 
Neomycin (PLD inhibitor), for example, can inhibit 
mTORC1 activation, whereas phospholipase C inhibitor, 
known as U73122, does not inhibit mTORC1 activation 
mediated by mechanical overload. The administration of 
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44 A.K. Yamada et al.
 Journal of Receptors and Signal Transduction
1-Butanol (PLD inhibitor) can block mTORC1 signaling, 
but 2-Butanol does not have any effect on mTORC1 acti-
vated by mechanical overload (eccentric contractions 
and passive stretching) (10).
A follow-up study of the same group showed that 
eccentric contractions induce muscle growth and 
increases PA levels (11). Interestingly, only the muscles 
that displayed hypertrophy obtained increases in PA in 
response to the stimuli, showing that PA is important in 
load-induced muscle hypertrophy (11).
In this context, screening other potential enzymes 
that regulate mTORC1/PA interface certainly will pro-
vide outstanding foundation. It is known that PA can be 
produced by phosphatidiycoline (PC), lysophosphatidic 
acid (LPA) and diacylgrycerol (DAG) (3). Thus, PA can be 
regulated trough enzymes that it degrades, such as phos-
pholipase A (PLA) and phosphatidic acid phosphatase 
(PAP) (3). DAC activates mTORC1 and this enzyme is 
blocked when binding domain of PA is mutated (3). To 
our knowledge there is no available evidence for a role of 
PLA on mTORC1 regulation in skeletal muscle biology, 
and then these mechanisms will also be important topics 
to be investigated.
Final considerations
In the last decade, a fantastic progress occurred in skel-
etal muscle biology. Even after years of investigation, the 
mechanical sensor remains unknown due to a large num-
ber of factors that drives skeletal muscle hypertrophy. 
The paradigm that growth factor signaling is necessary 
has been set aside, giving rise to the emergent mechan-
otransduction knowledge. The groundbreaking discovery 
that mTORC1 is activated by PA undeniably opened novel 
possibilities of investigation. The identification of other 
enzymes involved in mTORC1/PA interface will also be 
active topics to be explored in the coming years. Thus, 
the elucidation of these mechanisms will provide novel 
insights of how mechanical information is converted into 
biochemical events. In future, these findings will provide 
foundation of anti-atrophic therapies with the main goal 
to recapitulate anabolic exercise. This set of knowledge 
will open new avenues in the treatment of wasting condi-
tions observed in the natural course of sarcopenia and in 
diseases such as AIDS, cancer, sepsis, renal failure, heart 
failure and muscular dystrophies.
Acknowledgments
The authors would like to thank the Fundação de 
Amparo à Pesquisa do Estado de São Paulo (FAPESP – 
2008/57836-0) for funding to C. R. B. Jr.
Declaration of interest
The authors declare no conflicts of interest.
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	Mechanotransduction pathways in skeletal muscle hypertrophy
	Abstract
	Background
	mTORC1 and S6K1 drive hypertrophy
	The irrelevant growth factor
	Phosphatidic acid: “new kid on the block”?
	Final considerations
	Acknowledgments
	References