Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction
Se-Jin Lee
Se-Jin Lee
Published May 3, 2021
Citation Information: J Clin Invest. 2021;131(9):e148372. https://doi.org/10.1172/JCI148372.
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Review

Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction

Abstract

Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications.

Authors

Se-Jin Lee

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Figure 1

Processing of MSTN.

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Processing of MSTN. The MSTN precursor protein is cleaved by furin prote...
The MSTN precursor protein is cleaved by furin proteases to generate an N-terminal propeptide (blue) and a C-terminal dimer (orange), which is the actual signaling molecule. The propeptide remains noncovalently bound to the C-terminal dimer and maintains MSTN in an inactive, latent state. Latent MSTN is activated by proteolytic cleavage of the propeptide immediately N-terminal to aspartate residue 76 by members of the BMP-TLD family of metalloproteases, which frees up the C-terminal dimer to bind to cell surface receptors. Adapted with permission from the Annual Review of Cell and Developmental Biology (112).