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 biological sex and ovarian hormones on these outcomes remains poorly understood. Here, we examined male, intact female, and ovariectomized (OVX) female mice at 12 wk following VML to determine how biological sex and the loss of ovarian hormones affect whole body metabolism, functional recovery, and tissue remodeling. Males postinjury relied on greater lipid oxidation postprandially, whereas 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. Biological sex did not influence maximal isometric torque or contractile properties following VML, which accompanied similarities in mitochondrial content [i.e., citrate synthase, pyruvate dehydrogenase (PDH) activity]. Females exhibited greater complex II activity than males, whereas 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 biological 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 biological sex and ovarian hormones in preclinical studies and therapeutic strategies for regenerative interventions.NEW & NOTEWORTHY This study combined ovariectomy and volumetric muscle loss injury model to investigate if ovarian hormones play a protective role in females during the sequelae of traumatic skeletal muscle injury. The loss of ovarian hormones induces whole body and cellular metabolic inflexibility and worsened functional recovery, identifying ovarian hormones as key regulators of VML-induced metabolic pathophysiology.