Myostatin Signals through a Transforming Growth Factor β-Like Signaling Pathway To Block Adipogenesis

Abstract

Myostatin, a transforming growth factor ␤ (TGF-␤) family member, is a potent negative regulator of skeletal muscle growth. In this study we characterized the myostatin signal transduction pathway and examined its effect on bone morphogenetic protein (BMP)-induced adipogenesis. While both BMP7 and BMP2 activated transcription from the BMP-responsive I-BRE-Lux reporter and induced adipogenic differentiation, myostatin inhibited BMP7-but not BMP2-mediated responses. To dissect the molecular mechanism of this antagonism, we characterized the myostatin signal transduction pathway. We showed that myostatin binds the type II Ser/ Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T␤RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-␤-like signaling pathway. We demonstrated that myostatin prevents BMP7 but not BMP2 binding to its receptors and that BMP7-induced heteromeric receptor complex formation is blocked by competition for the common type II receptor, ActRIIB. Thus, our results reveal a strikingly specific antagonism of BMP7-mediated processes by myostatin and suggest that myostatin is an important regulator of adipogenesis.Mesenchymal stem cell differentiation is generally thought to be initiated by the inductive action of specific growth factors, and abundant evidence demonstrates that transforming growth factor ␤ (TGF-␤) superfamily members can profoundly regulate these processes (12,17,18,34,58). For instance, TGF-␤ can inhibit adipogenesis and myogenesis while bone morphogenetic proteins (BMPs) can promote chondrogenesis, osteogenesis, and adipogenesis. Myostatin (previously known as growth and differentiation factor 8 [GDF8]) is a key critical regulator of skeletal muscle development (26). Myostatin-null mice display widespread increases in muscle mass (36) and decreased body fat accumulation (28,38), and inhibition of myostatin with blocking antibodies increases muscle mass (8). Myostatin function appears to be well conserved, since mutations in the myostatin gene have been identified in the doublemuscled Belgium Blue and Piedmontese cattle breeds (37). Consistent with this, myostatin mRNA is first expressed in somites, in the myotome layer that gives rise to skeletal muscle (36), and is highly expressed in skeletal muscle at later developmental stages and in adults and has been detected in both fetal and adult heart and in adipose tissue (36, 50). Of note, systemic administration of myostatin to adult mice results in a cachexia-like syndrome that is associated with a profound loss of both muscle and fat (64). Since decreased fat accumulation is observed both in knock-out mice that lack myostatin and in wild-type adult mice in which myostatin has been systemically administered (28, 38), it appears that myostatin may play distinct physiological roles during early development and during adult homeostatic processes.Like all TGF-␤ superfamily members, myostatin is synthesized in a precursor form that is proteolyti...

Reconstitution and Analysis of Soluble Inhibin and Activin Receptor Complexes in a Cell-free System

“…Receptor complex specificity can also be altered through accessory proteins such as Cripto, which suppress binding of activin to ActRII and promote nodal binding (33). In this regard, activin type II receptors are a particularly interesting example of promiscuity within this family since they participate in signal transduction for activins, myostatin, nodal, and certain bone morphogenetic proteins (BMPs) through alterations in their complex partners (15,34). Taken together, these results demonstrate that the precise composition of signaling complexes on .…”

Resistance to body fat gain in ‘double-muscled’ mice fed a high-fat diet

“…In vitro studies have shown that myostatin can inhibit adipocyte differentiation in 3T3-L1 mouse preadipocytes, 7 and myostatin may also inhibit Reduced body fat gain in double-muscled Mice MW Hamrick et al BMP-7 mediated adipogenesis by binding to the same receptor as BMP-7, the activin IIB receptor. 8 These data suggest that loss of myostatin function should increase adipogenesis, but the in vivo data obviously do not support this prediction. Alternatively, myostatin has been observed to promote adipogenesis in multipotential mesenchymal cells, suggesting that loss of myostatin function may directly suppress adipocyte differentiation.…”

Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity

“…TGF-␤1 has been shown to block preadipocyte differentiation in vitro (2), and transgenic overexpression of TGF-␤1 in mice led to lipodystrophy (3). The TGF-␤ protein myostatin, also known as GDF8, has been shown to regulate adipogenesis in vitro either directly or indirectly by blocking BMP signaling (4,5). In agreement with a role in adipocyte differentiation, targeted ablation of myostatin in mice reduced accumulation of adipose tissue and weight gain in mouse models of obesity (6).…”