MYOSTATIN

Myostatin: Muscle Regulation And Potential Therapeutic Target

Myostatin: Muscle Regulation And Potential Therapeutic Target

Introduction

Adult skeletal muscle is a dynamic tissue undergoing a continuous round of stem cell activation, proliferation and differentiation. A number of myogenic cell types at various stages of development exist in muscle tissue at any one time: satellite cells (muscle stem cells), myoblasts, myocytes (activated proliferating myoblasts), differentiated myocytes and finally, the muscle syncitia that make up fast and slow twitch muscle fibers (Fig. 1A). Atrophy of muscle cells or of the motor neurons that innervate them results in muscular wasting and loss of function. The regulation of skeletal muscle homeostasis is tightly controlled to maintain a delicate balance of cell types within the tissue at all times. Myostatin (MSTN), also known as GDF-8, is a member of the TGF-b family of growth and differentiation factors [1]. It serves to negatively regulate stem cell activation [2] as well as promote survival of the muscle syncitia. Naturally occurring null mutations in the myostatin gene of cows, sheep, dogs, swine and humans are hyper muscular with myostatin null mice displaying a similar phenotype [3]. In particular, dogs carrying at least one mutant myostatin allele displayed enhanced racing performance, confirming a functional benefit to loss of myostatin [4]. Correspondingly, overexpression of myostatin in adult mice causes profound muscle and fat loss without an alteration in satiety [5] and in humans, myostatin levels are elevated in sarcopenic individuals [6]. Myostatin is produced in increasing amounts as cells progress through the developmental cascade such that the rate of satellite cell activation, proliferation and differentiation is negatively regulated by signals arising from the fully developed muscle cells. The complex signal transduction network through which myostatin regulates myoblast maturation is described in Figure 1A and is nicely reviewed by Joulia-Ekaza and Cabello [3] and references therein. Myostatin binds to and activates a heterodimeric complex of activin receptor 2B (Acvr2b) andALK4 orALK5 that is expressed by myogenic stem cells and proliferating myoblasts. Acvr2b receptor activation triggers multiple intracellular signaling cascades including the SMAD and MAPK pathways that activate the AKT and p21/Rb pathways and inhibit expression of the muscle regulatory factors (MRFs). MRFs, including MyoD, positively regulate myostatin gene transcription during myocyte maturation. This results in the inhibition of satellite cell activation, blocking of the cell cycle in proliferating myoblasts and consequently slows further myogenesis. Myostatin signaling also prolongs the survival of fully differentiated muscle syncitia via the p53 pathway and stabilizes the acetylcholine receptors that underpin neuromuscular junctions. The myostatin signaling cascade also forms an autoregulatory loop to repress its own transcription as well as to degrade the myostatin/Acvr2b signaling complex [3]. This complex mode of action creates a careful balance of differentiated cell types for optimal muscular function as well as for rapid regeneration of damaged muscle tissue.

Figure 1. (A) Myostatin (MSTN) levels tightly regulate skeletal muscle cell homeostasis in adult tissue.

Myostatin is synthesized and secreted by muscle cells in increasing trace amounts as they proceed through the myoblast activation, proliferation and differentiation ...