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Review
. 2023 Feb 10:85:269-291.
doi: 10.1146/annurev-physiol-012422-112116. Epub 2022 Oct 20.

Myostatin: A Skeletal Muscle Chalone

Se-Jin Lee  1   2
Affiliations
Review

Myostatin: A Skeletal Muscle Chalone

Se-Jin Lee. Annu Rev Physiol. .

Abstract

Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-β family member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears to have all of the salient properties of a chalone, which is a term proposed over a half century ago to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it also operates in other tissues.

Keywords: GDF-8; activin; growth; latency; tissue size; transforming growth factor-β.

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Figures

Figure 1
Figure 1
Regulation of muscle mass by myostatin (MSTN), activin A, and bone morphogenetic proteins (BMPs). Following proteolytic processing of the precursor protein, MSTN remains noncovalently bound to its N-terminal propeptide, which maintains MSTN in an inactive, latent state. The latent MSTN complex is activated by members of the BMP-1 family of metalloproteases: BMP-1, TLD (tolloid), TLL-1 (tolloid-like 1), and TLL-2. MSTN is also regulated extracellularly by other inhibitory binding proteins, including GASP-1 (growth and differentiation factor–associated serum protein-1), GASP-2, follistatin (FST), and FSTL-3 (follistatin-like 3) (also called FLRG or follistatin-related gene). Follistatin and FSTL-3 are also capable of binding and inhibiting activin A. LTBP-3 (latent TGF-β binding protein-3) may play a role in regulating the processing of the MSTN precursor protein. MSTN and activin A signal by binding initially to the activin type 2 receptors, ACVR2 (activin receptor type 2) and ACVR2B, which leads to engagement of the type 1 receptors, ALK4 (activin receptor–like kinase-4) and ALK5. ALK4 and ALK5 phosphorylate and activate the SMAD (SMA and MAD-related) proteins, SMAD2 and SMAD3, which form a complex with SMAD4 and act to inhibit muscle growth. Although the specific components utilized by BMPs in muscle have not been completely elucidated, BMPs are capable of binding to the type 1 receptors, ALK3 and ALK6, and then engaging the type 2 receptors, BMPR2 (bone morphogenetic protein receptor type 2), ACVR2, and ACVR2B. ALK3 and ALK6 phosphorylate and activate SMAD1, SMAD5, and SMAD8, which form a complex with SMAD4 and act to induce muscle growth. Components shown in green act to induce muscle growth, and components shown in pink act to inhibit muscle growth.
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