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

Winbanks, Catherine E.; Weeks, Kate L.; Thomson, Russell; Sepulveda, Patricio V.; Beyer, Claudia; Qian, Hongwei; Chen, Justin L.; Allen, J. M.; Lancaster, Graeme I.; Febbraio, Mark A.; Harrison, Craig A.; McMullen, Julie R.; Chamberlain, Jeffrey S.; Gregorevic, Paul

doi:10.1083/jcb.201109091

Cited by 172 publications

(206 citation statements)

References 64 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…In skeletal muscle, overexpression of constitutively active Smad3 efficiently attenuated hypertrophy, whereas Smad3-null mice expressed increased susceptibility to TAC-induced hypertrophy in the heart. 31,32 Consistent with these studies, we have identified a Pak1-dependent Smad3 antihypertrophic pathway through the transcriptional regulation of Fbxo32. Furthermore, our study has identified a specific potent singular AGAC -286 -binding site responsible for Fbxo32 expression.…”

Section: Discussionsupporting

confidence: 67%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

View full text Add to dashboard Cite

Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC -286 -binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

show abstract

Section: Discussionsupporting

confidence: 67%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

View full text Add to dashboard Cite

show abstract

“…This occurs at least partially through the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway (27,50,61). A recent microarray study suggested that decreased oxidative capacity occurs after blocking of myostatin and activins by sActRIIB-Fc (47), but no further signaling analysis was conducted.…”

mentioning

confidence: 99%

“…In healthy adult muscle, blocking of myostatin and other TGF␤ family members increases protein synthesis (58,61) and muscle size (18,24,27,32,45,50,61,68). This occurs at least partially through the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway (27,50,61).…”

mentioning

confidence: 99%

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Hulmi

Oliveira

Silvennoinen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

136

View full text Add to dashboard Cite

Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1–2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.

show abstract

“…Matn2 has been shown to be regulated by Smad signaling in other cell types (Ichikawa et al, 2008), and TGF-b and Smad2/3 signaling is known to inhibit myogenic differentiation and muscle growth (Gardner et al, 2011;Sartori et al, 2009;Winbanks et al, 2012). Thus, we next assessed whether Matn2 and TGF-b signaling might regulate one another in differentiating myoblasts.…”

Section: Tgf-b Signaling Represses Matn2 Expression and Myoblast Diffmentioning

confidence: 99%

Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration

Deák¹,

Mátés²,

Korpos³

et al. 2014

Development

View full text Add to dashboard Cite

BSTRACTHere, we identify a role for the matrilin-2 (Matn2) extracellular matrix protein in controlling the early stages of myogenic differentiation. We observed Matn2 deposition around proliferating, differentiating and fusing myoblasts in culture and during muscle regeneration in vivo. Silencing of Matn2 delayed the expression of the Cdk inhibitor p21 and of the myogenic genes Nfix, MyoD and Myog, explaining the retarded cell cycle exit and myoblast differentiation. Rescue of Matn2 expression restored differentiation and the expression of p21 and of the myogenic genes. TGF-b1 inhibited myogenic differentiation at least in part by repressing Matn2 expression, which inhibited the onset of a positive-feedback loop whereby Matn2 and Nfix activate the expression of one another and activate myoblast differentiation. In vivo, myoblast cell cycle arrest and muscle regeneration was delayed in Matn2 2/2 relative to wild-type mice. The expression levels of Trf3 and myogenic genes were robustly reduced in Matn2 2/2 fetal limbs and in differentiating primary myoblast cultures, establishing Matn2 as a key modulator of the regulatory cascade that initiates terminal myogenic differentiation. Our data thus identify Matn2 as a crucial component of a genetic switch that modulates the onset of tissue repair.

show abstract

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

Abstract: Smad3/Akt/mTOR/S6K/S6RP signaling plays a critical role in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms.

Cited by 172 publications

References 64 publications

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration

Contact Info

Product

Resources

About