Dataset Information

Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.

ABSTRACT: 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.

SUBMITTER: Winbanks CE

PROVIDER: S-EPMC3384410 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.

Winbanks Catherine E CE Weeks Kate L KL Thomson Rachel E RE Sepulveda Patricio V PV Beyer Claudia C Qian Hongwei H Chen Justin L JL Allen James M JM Lancaster Graeme I GI Febbraio Mark A MA Harrison Craig A CA McMullen Julie R JR Chamberlain Jeffrey S JS Gregorevic Paul P

The Journal of cell biology 20120618 7

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 mT ...[more]

PMID: 22711699

Similar Datasets

Project description:BackgroundSkeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF-β) superfamily, including activin A, which causes atrophy. TGF-β superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.MethodsTo elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB).ResultsFst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.ConclusionsWe here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-β superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans.

Project description:Myostatin (MSTN) is a well-known negative growth factor of muscle mass, and studies have shown that MSTN-inhibition would be a potential strategy to treat muscle atrophy seen in various clinical conditions. Recent studies suggest that MSTN-inhibition induces skeletal muscle hypertrophy through up-regulation of the anabolic Akt/mTOR pathway. Therefore, it was hypothesized that the muscle hypertrophy induced by MSTN-inhibition would be suppressed by the administration of rapamycin (RAP), a mTOR suppressor. A MSTN transgenic mouse strain (MSTN-pro), which is characterized by a postnatal hyper-muscularity due to MSTN inhibition through transgenic overexpression of MSTN propeptide, was used in producing experimental animals. Five-week-old male heterozygous MSTN-pro mice and wild-type littermates were administered with 0 or 3?mg/kg body weight of RAP intraperitoneally every other day for 4 weeks. The effects of RAP on muscle growth, mRNA abundance of signaling components of the Akt/mTOR pathway, and myogenic regulatory factors (MyoD, Myf5, MyoG, and Mrf4) were examined in comparison to wild-type mice. Body weight gain of MSTN-pro mice was significantly greater than that of wild-type mice. RAP suppressed body weight gain and muscle mass in both MSTN-pro and wild-type mice. The extent of both body weight and muscle mass suppression was significantly greater in MSTN-pro mice than in wild-type mice. Real-time qPCR analysis showed that mRNA abundance of the signaling molecules of the Akt/mTOR pathway, including Akt, p70S6K, and 4E-BP1, were significantly higher in MSTN-pro mice. RAP treatment decreased mRNA abundance of Akt, p70S6K and 4E-BP1 only in MSTN-pro mice. mRNA abundances of MyoD and MyoG were not affected by MSTN suppression or RAP treatment. mRNA abundance of Myf5 was decreased by RAP, but not affected by MSTN suppression. mRNA abundance of Mrf4 was decreased by MSTN suppression. RAP treatment decreased mRNA abundance of Mrf4 only in wild type mice. Results of this study indicate that transcriptional regulation of signaling components of the Akt/mTOR pathway and myogenic regulatory transcription factor Mrf4 is involved in the enhancement of skeletal muscle mass induced by MSTN suppression.

Dataset Information

Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.

Publications

Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets