The role of myostatin and related factors in muscle hypertrophy and atrophy

Myostatin, also known as growth and differentiation factor-8, is a member of the TGF-β family and is mainly produced by skeletal muscle. Myostatin circulates in the serum in a latent form, whereas it acts almost exclusively on skeletal muscle. Deletion or pharmacological blockade of myostatin induces skeletal muscle hypertrophy, indicating that myostatin limits the growth of skeletal muscle and represents one of the major determination factors of skeletal muscle mass. Myostatin is structurally related to growth and differentiation factor 11 (GDF11) and activins. GDF11 is also a regulator of skeletal muscle, although it also acts on bone, heart and other tissues. Activins are pleiotropic growth factors that regulate hormone production from pituitary and reproduction. Activins are also involved in the regulation of skeletal muscle mass, but the effect is lower compared with that of myostatin. Myostatin binds to activin type IIA (ActRIIA) or type IIB (ActRIIB) receptors, following which the ActRIIs phosphorylate activin receptor-like kinases 5 and 4 (ALK5 and ALK4). Similar to activins, GDF11 and TGF-β, Smad2/3 are subsequently phosphorylated by type I kinase activity in the cell, resulting in the formation of a complex with Smad4. The Smad complexes translocate into the nucleus to regulate transcription in a tissue-specific manner. However, the mechanism by which myostatin limits skeletal muscle growth remains unknown. A previous study showed that myostatin acts on myofibers rather than satellite cells, while another reported that myostatin acts on satellite cells. Myostatin inhibits muscle protein synthesis by inhibiting the Akt/mammalian target of rapamycin (mTOR) pathway. Several miRNAs are involved in myostatin signaling. Among them, miR-486, a positive regulator of the IGF-1/Akt pathway, is an intermediate molecule that connects myostatin signaling and the Akt/mTOR pathway in the regulation of skeletal muscle mass. Skeletal muscle atrophy occurs in sarcopenia, cachexia, intractable muscular dystrophies and certain drug treatments. Myostatin inhibiton is considered to be a rational therapeutic strategy for the prevention of muscle atrophy. Neutralizing antibodies against myostatin, or ActRIIs, a soluble extracellular domain of ActRIIs and chemical kinase inhibitors for ALK4/5/7 have been developed as inhibitors of myostatin signaling. Their effectiveness in increasing skeletal muscle mass and preventing muscle atrophy have been studied. Furthermore, follistatin and its derivatives, follistatin-related gene and myostatin propeptide, which are natural inhibitors of myostatin, are also good candidates for myostatin blockade to prevent skeletal muscle atrophy. In this chapter, we discuss the outline of myostatin and related TGF-β family members as regulators of muscle mass and function and their role in muscle hypertrophy and atrophy.