Myostatin Modulation in Skeletal Muscle Development

Myostatin, a member of the transforming growth factor-β superfamily, is a principal negative regulator of skeletal muscle growth and homeostasis. By binding to activin type II receptors, myostatin activates intracellular Smad2/3 signalling, which leads to cell-cycle arrest in myoblasts and suppression of myogenic regulatory factors. Genetic disruption or pharmacological inhibition of myostatin enhances muscle fibre hyperplasia and hypertrophy, improves metabolic profiles and increases force production. Conversely, elevated myostatin expression is associated with muscle wasting in ageing, disuse and neuromuscular diseases. Modulation strategies have ranged from neutralising antibodies and receptor decoys to gene editing approaches in livestock and model organisms. A deeper understanding of the interplay between myostatin and other TGF-β ligands, its binding partners such as follistatin, and downstream epigenetic regulators is revealing new avenues for therapeutic intervention in muscle degenerative conditions, metabolic disorders and for the enhancement of livestock production.

Research from Nature Portfolio

Recent studies have identified activin A as a second key negative regulator of muscle mass; selective inhibition of both activin A and myostatin yields pronounced hypertrophy and force gains in murine and primate models, while avoiding off-target effects of broad TGF-β blockade. Investigations in neuromuscular disease models reveal that chronic wasting is accompanied by downregulated expression of myostatin, its receptor and coreceptors, alongside elevated levels of antagonists such as follistatin; reactivation of the pathway by genetic correction of underlying mutations restores muscle mass and function, offering insight into previous disappointments in clinical trials of anti-myostatin agents. In a large-animal model, targeted gene editing of the myostatin locus in pigs induces a double-muscled phenotype with hyperplastic muscle growth and reduced adiposity, demonstrating the translational potential of precise myostatin modulation for both agricultural and biomedical research.

Myostatin Modulation in Skeletal Muscle Development publication trend

The graph below shows the total number of articles in myostatin modulation in skeletal muscle development across all publications each year (not limited to Nature Index journals).

Technical terms

Myostatin (MSTN): A transforming growth factor-β family member that inhibits muscle cell proliferation and differentiation.

Myoblast: A precursor muscle cell that differentiates into a myotube during myogenesis.

Hyperplasia: An increase in the number of muscle fibres, leading to greater muscle mass.

Autocrine signalling: A mode of cell communication where a cell secretes factors that act on itself.

Paracrine signalling: A form of cell communication in which secreted factors affect neighbouring cells.

Smad proteins: Intracellular mediators of transforming growth factor-β signalling that regulate gene expression.

Histone acetylation: An epigenetic modification that loosens chromatin structure to promote gene transcription.

Activin A: A cytokine in the TGF-β family that, alongside myostatin, regulates muscle mass.

References

1. SYISL Knockout Promotes Embryonic Muscle Development of Offspring by Modulating Maternal Gut Microbiota and Fetal Myogenic Cell Dynamics. Advanced Science (2024).
2. Myostatin regulates energy homeostasis through autocrine- and paracrine-mediated microenvironment communications. Journal of Clinical Investigation (2024).
3. Myostatin, a Negative Regulator of Muscle Growth, Functions by Inhibiting Myoblast Proliferation*. Journal of Biological Chemistry (2000).
4. Myostatin Inhibits Myoblast Differentiation by Down-regulating MyoD Expression*. Journal of Biological Chemistry (2002).
5. Targeted mutations in myostatin by zinc-finger nucleases result in double-muscled phenotype in Meishan pigs. Scientific Reports (2015).
6. Activin A more prominently regulates muscle mass in primates than does GDF8. Nature Communications (2017).
7. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches. Nature Communications (2017).