Biological sex divergence in transcriptomic profiles during the onset of hindlimb unloading-induced atrophy

Abstract

Disuse-induced muscle atrophy is a common clinical problem observed mainly in older adults, intensive care units patients, or astronauts. Previous studies presented biological sex divergence in progression of disuse-induced atrophy along with differential changes in molecular mechanisms possibly underlying muscle atrophy. The aim of this study was to perform transcriptomic profiling of male and female mice during the onset and progression of unloading disuse-induced atrophy. Male and female mice underwent hindlimb unloading (HU) for 24, 48, 72 and 168h (n=8/group). Muscles were weighed for each cohort and gastrocnemius was used for RNA-sequencing analysis. Females exhibited muscle loss as early as 24h of HU, while males after 168h of HU. In males, pathways related to proteasome degradation were upregulated throughout 168-h HU, while in females these pathways were upregulated up to 72-h HU. Lcn2, a gene contributing to regulation of myogenesis, was upregulated by 6.46-19.86-fold across all time points in females only. A reverse expression of Fosb, a gene related to muscle degeneration, was observed between males (4.27-fold up) and females (4.57-fold down) at 24-h HU. Mitochondrial pathways related to TCA cycle were highly downregulated at 168h of HU in males, while in females this downregulation was less pronounced. Collagen-related pathways were consistently downregulated throughout 168-h HU only in females, suggesting a potential biological sex-specific protective mechanism against disuse-induced fibrosis. In conclusion, females may have protection against HU-induced skeletal muscle mitochondrial degeneration and fibrosis through transcriptional mechanisms, although they may be more vulnerable to HU-induced muscle wasting compared to males.