Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures

  1. Marianne E Emmert
  2. Parul Aggarwal
  3. Kritton Shay-Winkler
  4. Se-Jin Lee
  5. Qingnian Goh  Is a corresponding author
  6. Roger Cornwall  Is a corresponding author
  1. University of Cincinnati, United States
  2. Cincinnati Children's Hospital Medical Center, United States
  3. Jackson Laboratory, United States

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Marianne E Emmert

    Department of Medical Sciences, University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  2. Parul Aggarwal

    Division of Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    No competing interests declared.
  3. Kritton Shay-Winkler

    Division of Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    No competing interests declared.
  4. Se-Jin Lee

    Jackson Laboratory, Farmington, United States
    Competing interests
    Se-Jin Lee, consulting fees from Biohaven Pharmaceuticals, Inc., and Alnylam Pharmaceuticals, Inc. Payment/honoraria: Regeneron Pharmaceuticals, Inc. Patent: Therapeutics targeting transforming growth factor beta family signaling".".
  5. Qingnian Goh

    Division of Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    Qingnian.Goh@cchmc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4108-2957
  6. Roger Cornwall

    Division of Orthopaedic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    Roger.Cornwall@cchmc.org
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (R01HD098280-01)

  • Roger Cornwall

Cincinnati Children's Hospital Medical Center (Junior Cooperative Society)

  • Roger Cornwall

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All rodents were handled according to approved institutional animal care and use committee (IACUC) protocols (#2020-0067) of the Cincinnati Children's Hospital Medical Center, and every effort was made to minimize suffering.

Reviewing Editor

  1. Christopher Cardozo, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: June 16, 2022
  2. Preprint posted: June 18, 2022 (view preprint)
  3. Accepted: October 31, 2022
  4. Accepted Manuscript published: October 31, 2022 (version 1)

Copyright

© 2022, Emmert et al.

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

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  1. Marianne E Emmert
  2. Parul Aggarwal
  3. Kritton Shay-Winkler
  4. Se-Jin Lee
  5. Qingnian Goh
  6. Roger Cornwall
(2022)
Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures
eLife 11:e81121.
https://doi.org/10.7554/eLife.81121
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