Volumetric muscle loss (VML) is a skeletal muscle injury resulting from traumatic or surgical tissue loss that exceeds the muscle’s innate regenerative capacity. The metabolic consequences of VML have only recently been investigated, with emerging evidence suggesting females preserve metabolic adaptability after injury. However, it remains unknown whether sex-specific mechanisms, particularly ovarian hormones, underlie the distinct metabolic responses between males and females post-VML. This study aimed to investigate if the loss of ovarian hormones can explain the sex-specific differences VML pathophysiology, including whole-body metabolism and lipid remodeling. At ~10 weeks of age, adult C57Bl/6 female mice were randomized to undergo bilateral ovariectomy (OVX; n=11) or remain intact (n=13). At ~12 weeks of age, all mice (n=37; n=24 female, n=13 male) underwent VML to the posterior compartment (gastroc, soleus, plantaris) of the hindlimb. Post-prandial whole-body metabolism and glucose tolerance was evaluated at ~22 weeks of age. Body composition was assessed via EchoMRI at ~23 weeks of age. Terminally at ~24 weeks of age, in vivo muscle function was measured, and muscle and gonadal adipose tissue were saved for analyses. All data was analyzed by one-way ANOVA. Post-prandially, males following VML relied on greater lipid oxidation (p=0.003), while females maintained robust carbohydrate oxidation and dynamic metabolic flexibility (p< 0.0001). The loss of ovarian hormones post-VML resulted in ~2.5-fold greater adiposity (p< 0.0001) and blunted the post-prandial glucose responsiveness observed in females (p< 0.0001). Maximal isometric torque was not influence by biologic sex following VML, though the loss of ovarian hormones resulted in a ~24% and ~26% decrease in torque compared to males and females, respectively (p=0.005). Mitochondrial content and enzymatic activity were assessed in the remaining muscle. Despite comparable mitochondrial content (citrate synthase activity), the loss of ovarian hormones decreased complex I activity compared to males and females (p< 0.0001). Complex II activity was influenced by biologic sex following VML, with males exhibiting an ~18% impairment compared to females (p=0.044). Histological evaluation of lipid accumulation and remodeling was conducted. The loss of ovarian hormones resulted in comparable lipid accumulation to females, while ~37% greater than males following VML (p=0.010). Perilipin 2 and 5 were evaluated in the muscle remaining following VML to determine whether proximity to the VML defect influenced expression. Together, divergent metabolic responses between males and females occur following VML, specifically substrate utilization and mitochondrial function. Ovarian hormones may, in part, underlie the differential metabolic trajectories following injury, highlighting that biologic sex should be considered when evaluating therapeutic strategies for traumatic muscle injuries. Funding: NIH R01-AR078903 (JAC and SMG), K02-AG081488 (SMG), T32-AR007612 (ASB); University of Minnesota’s Office of Undergraduate Research (CGF) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Bruzina et al. (2026) studied this question.