Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.
Follistatin is essential for skeletal muscle development and growth, but the intracellular signaling networks that regulate follistatin-mediated effects are not well defined. We show here that the administration of an adeno-associated viral vector expressing follistatin-288aa (rAAV6:Fst-288) markedly increased muscle mass and force-producing capacity concomitant with increased protein synthesis and mammalian target of rapamycin (mTOR) activation. These effects were attenuated by inhibition of mTOR or deletion of S6K1/2. Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms.
Division of Metabolism and Obesity, Baker IDI Heart and Diabetes Institute, Victoria 3004, Australia.
Catherine E
CE
Winbanks
Kate L
KL
Weeks
Rachel E
RE
Thomson
Patricio V
PV
Sepulveda
Claudia
C
Beyer
Hongwei
H
Qian
Justin L
JL
Chen
James M
JM
Allen
Graeme I
GI
Lancaster
Mark A
MA
Febbraio
Craig A
CA
Harrison
Julie R
JR
McMullen
Jeffrey S
JS
Chamberlain
Paul
P
Gregorevic
D000818:Animals; D038681:Follistatin / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D038681:Follistatin; C525912:Mstn protein, mouse; D055435:Myostatin; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases