PT  - JOURNAL ARTICLE
AU  - Marianne E Emmert
AU  - Parul Aggarwal
AU  - Kritton Shay-Winkler
AU  - Se-Jin Lee
AU  - Qingnian Goh
AU  - Roger Cornwall
TI  - Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures
AID  - 10.1101/2022.06.17.496582
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.17.496582
4099  - http://biorxiv.org/content/early/2022/06/18/2022.06.17.496582.short
4100  - http://biorxiv.org/content/early/2022/06/18/2022.06.17.496582.full
AB  - 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 StatementThe authors have declared no competing interest.NBPIneonatal brachial plexus injuryGDF8growth differentiation factor-8TGF-βtransforming growth factor betaMSTNmyostatinACVR2B-Fcsoluble activin receptor type IIB; Akt, protein kinase BmTORmammalian target of rapamycinp70S6KS6 kinaseSmad 2 & 3mothers against decapentaplegic homolog 2 & 3GAPDHglyceraldehyde-3-phosphate dehydrogenaseDPBSDulbecco’s phosphate-buffered saline