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Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures

Marianne E Emmert, Parul Aggarwal, Kritton Shay-Winkler, Se-Jin Lee, Qingnian Goh, Roger Cornwall
doi: https://doi.org/10.1101/2022.06.17.496582
Marianne E Emmert
1Department of Medical Sciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Parul Aggarwal
2Division of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Kritton Shay-Winkler
2Division of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
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Se-Jin Lee
3The Jackson Laboratory, Farmington, CT, USA
4Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
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Qingnian Goh
2Division of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
5Department of Orthopaedic Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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  • For correspondence: Qingnian.Goh@cchmc.org Roger.Cornwall@cchmc.org
Roger Cornwall
2Division of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
5Department of Orthopaedic Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
6Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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  • For correspondence: Qingnian.Goh@cchmc.org Roger.Cornwall@cchmc.org
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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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 18, 2022.
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Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures
Marianne E Emmert, Parul Aggarwal, Kritton Shay-Winkler, Se-Jin Lee, Qingnian Goh, Roger Cornwall
bioRxiv 2022.06.17.496582; doi: https://doi.org/10.1101/2022.06.17.496582
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Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures
Marianne E Emmert, Parul Aggarwal, Kritton Shay-Winkler, Se-Jin Lee, Qingnian Goh, Roger Cornwall
bioRxiv 2022.06.17.496582; doi: https://doi.org/10.1101/2022.06.17.496582

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