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Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures
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 proteostas...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873256/ https://www.ncbi.nlm.nih.gov/pubmed/36314781 http://dx.doi.org/10.7554/eLife.81121 |
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author | Emmert, Marianne E Aggarwal, Parul Shay-Winkler, Kritton Lee, Se-Jin Goh, Qingnian Cornwall, Roger |
author_facet | Emmert, Marianne E Aggarwal, Parul Shay-Winkler, Kritton Lee, Se-Jin Goh, Qingnian Cornwall, Roger |
author_sort | Emmert, Marianne E |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9873256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-98732562023-01-25 Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures Emmert, Marianne E Aggarwal, Parul Shay-Winkler, Kritton Lee, Se-Jin Goh, Qingnian Cornwall, Roger eLife Developmental Biology 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. eLife Sciences Publications, Ltd 2022-10-31 /pmc/articles/PMC9873256/ /pubmed/36314781 http://dx.doi.org/10.7554/eLife.81121 Text en © 2022, Emmert et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Emmert, Marianne E Aggarwal, Parul Shay-Winkler, Kritton Lee, Se-Jin Goh, Qingnian Cornwall, Roger Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title | Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title_full | Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title_fullStr | Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title_full_unstemmed | Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title_short | Sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
title_sort | sex-specific role of myostatin signaling in neonatal muscle growth, denervation atrophy, and neuromuscular contractures |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9873256/ https://www.ncbi.nlm.nih.gov/pubmed/36314781 http://dx.doi.org/10.7554/eLife.81121 |
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