GDF8

GDF8, also known as myostatin, is a protein belonging to the transforming growth factor beta (TGF-β) superfamily. It is encoded by the GDF8 gene in humans and is produced primarily by skeletal muscle fibers as a secreted precursor that is processed to a mature, active dimer. The protein functions as a circulating and locally acting regulator of muscle size.

Function and mechanism

Myostatin acts as a negative regulator of skeletal muscle growth. It inhibits myoblast proliferation and differentiation, thereby constraining muscle mass during development and helping maintain muscle size in adulthood. Signaling occurs when myostatin binds to activin type II receptors, such as ACVR2A and ACVR2B, activating a SMAD2/3-dependent transcriptional program. In addition to direct effects on muscle, myostatin can influence adipose tissue and metabolism. Its activity is modulated by binding proteins such as follistatin and by proteolytic processing, which controls the amount of active ligand.

Genetics and evolution

The MSTN/GDF8 gene was identified in the 1990s, and its discovery revealed a crucial role for myostatin in muscle regulation. Loss-of-function mutations in myostatin lead to markedly increased muscle mass in multiple species, most famously the double-muscled phenotype observed in certain cattle breeds and in laboratory mice lacking functional myostatin.

Clinical relevance

Because inhibiting myostatin can promote muscle growth, there has been active research into therapies for muscle-wasting conditions such as muscular dystrophy and cachexia. Various approaches, including antibodies, ligand traps, and follistatin-based strategies, have entered preclinical and clinical evaluation. Development has faced safety and efficacy challenges, with ongoing work aimed at balancing potential benefits against possible adverse effects on cardiac function, tendons, and metabolic regulation. Related topics include myostatin and the TGF-β family.