The impact of ovarian hormones on skeletal muscle remodeling and function following volumetric muscle loss

Volumetric muscle loss (VML) is an injury resulting in a substantial loss of skeletal muscle too severe for the body to repair. VML injuries lead to significant functional deficits and pathological fibrosis, and to date there is no clear clinical solution. Our study focuses on the effect of the loss of ovarian hormones on pathological fibrosis and lipid deposition following VML injuries. The loss of ovarian hormones is suspected to increase fibrosis and lipid development, which also occurs in VML injuries, thus it is hypothesized that loss of ovarian hormones combined with VML injury will result in a pathological fibrosis increase over adult females with circulating hormones. At ~10 weeks of age C57Bl/6 female mice (n=24) were randomized to ovariectomy (OVX) or remained intact, then at ~12 weeks of age all mice underwent VML injury (~20% to the gastrocnemius, plantaris, and soleus muscles). At ~24 weeks of age, maximal in vivo muscle torque of the plantarflexor muscle was evaluated and the muscle from all mice were harvested for histologic evaluation. The loss of ovarian hormones resulted in ~26% decrease in maximal isometric torque (p=0.002). Average rates of relaxation were lower with the loss of ovarian hormones compared to intact females following VML (p=0.009). Harvested gastrocnemius muscles were serially cryo-sectioned at the mid-belly (encompassing the VML injury) of the muscle and saved for further analyses. Muscle sections were stained for H&E, Masson’s Trichrome, Pico Sirius Red, and Oil-Red-O. Upon staining for H&E, more irregularly shaped myofibers were apparent with the loss of ovarian hormones compared to intact females, which may be indicative of a more fibrotic deposition. The loss of ovarian hormones did not influence muscle repair, which was assessed by calculating centrally located nuclei per square millimeter (p=0.224). Lipid accumulation within the muscle was quantified from Oil-Red-O staining. The loss of ovarian hormones did not induce greater lipid accumulation compared to intact females following VML (p=0.313). Observed fibrotic deposition with the loss of ovarian hormones, despite comparable lipid accumulation, suggests ovarian hormones may, in part, contribute to tissue remodeling following VML. Together, this highlights the importance of sex-specific hormones in the functional recovery from VML injury. 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.