Loss of ovarian hormones modulates sex-specific metabolic adaptations to volumetric muscle loss

Volumetric muscle loss (VML) results in persistent functional and metabolic deficits, yet the influence of biologic sex and ovarian hormones on these outcomes remains poorly understood. Here, we examined male, intact female, and ovariectomized (OVX) female mice at 12 weeks following VML to determine how biologic sex and the loss of ovarian hormones affects whole-body metabolism, functional recovery, and tissue remodeling. Males post-injury relied on greater lipid oxidation post-prandially, while females maintained robust carbohydrate oxidation and dynamic metabolic flexibility. The loss of ovarian hormones increased adiposity and impaired the sex-specific advantage in glucose responsiveness. Biologic sex did not influence maximal isometric torque or contractile properties following VML, which accompanied similarities in mitochondrial content (i.e., CS, PDH activity). Females exhibited greater complex II activity than males, while the loss of ovarian hormones decreased complex I and PDH activity. Despite comparable lipid accumulation in females with and without ovarian hormones, maximal isometric torque and contractile properties were impaired with the loss of ovarian hormones. Proximity to VML defect influenced lipid droplet proteins, specifically perilipin 2, though not affected by biologic sex or ovarian hormone loss. Collectively, these findings indicate that sex-specific differences in substrate utilization and mitochondrial function, mediated in part by ovarian hormones, may underlie the divergent metabolic and functional trajectories following VML. These results highlight the importance of considering biologic sex and ovarian hormones in pre-clinical studies and therapeutic strategies for regenerative interventions.