Document Type

Article

Publication Date

10-31-2022

Keywords

JGM, Male, Animals, Female, Mice, Myostatin, Contracture, Muscle, Skeletal, Denervation, Hypertrophy, Atrophy

JAX Source

Elife. 2022;11:e81121

ISSN

2050-084X

PMID

36314781

DOI

https://doi.org/10.7554/eLife.81121

Grant

We thank the following entities within Cincinnati Children’s Hospital Medical Center: the Veterinary Services Core for surgical assistance, the Confocal Imaging Core for microscope assistance, and the Millay Laboratory for discussions and feedback. We also thank Sharon Wang from the Preclinical Imaging Core (University of Cincinnati College of Medicine) for MicroCT assistance. This work was supported by grants to RC from the National Institutes of Health (NIH) (R01HD098280-01), as well as funding from the Cincinnati Children’s Hospital Division of Orthopaedic Surgery and Junior Cooper- ative Society. The respective funding sources were not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Abstract

Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that result from impaired longitudinal growth of denervated muscles. This deficit in muscle growth is driven by increased proteasome-mediated protein degradation, suggesting a dysregulation of muscle proteostasis. The myostatin (MSTN) pathway, a prominent muscle-specific regulator of proteostasis, is a putative signaling mechanism by which neonatal denervation could impair longitudinal muscle growth, and thus a potential target to prevent NBPI-induced contractures. Through a mouse model of NBPI, our present study revealed that pharmacologic inhibition of MSTN signaling induces hypertrophy, restores longitudinal growth, and prevents contractures in denervated muscles of female but not male mice, despite inducing hypertrophy of normally innervated muscles in both sexes. Additionally, the MSTN-dependent impairment of longitudinal muscle growth after NBPI in female mice is associated with perturbation of 20S proteasome activity, but not through alterations in canonical MSTN signaling pathways. These findings reveal a sex dimorphism in the regulation of neonatal longitudinal muscle growth and contractures, thereby providing insights into contracture pathophysiology, identifying a potential muscle-specific therapeutic target for contracture prevention, and underscoring the importance of sex as a biological variable in the pathophysiology of neuromuscular disorders.

Comments

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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