Female Mice Exhibit Faster Muscle Function Recovery After Fibrosis Inducing Injury

PURPOSE: Musculoskeletal injuries affect 65.8 million people annually in the U.S. and cost more than 176 billion dollars. After significant injury, muscle function rarely recovers to 100%. The lack of full muscle function restoration is affected by several factors including biological sex. Furthermore, the various measures of recovery are not well characterized between the sexes, including force, velocity, and fatigue. Further complicating repair is the interaction of the immune system with muscle in producing fibrosis. A major limitation of current lab-based models is that they produce minimal fibrosis. Our laboratory has recently conducted experiments using a newer injury model (glycerol injection) that amplifies inflammation and generates significant fibrosis. We hypothesized that inflammation/fibrosis is playing a sex-based role in measures of muscle function recovery. METHODS: Male and female mice were split into two groups. Mouse gastrocnemius muscle was injected with glycerol (experimental) or saline (control) on day 0. Muscle force production, contraction velocity, and muscle fatigue testing was performed 3 days (n = 14) and 12 days (n = 26) after injection, followed by hind-limb muscle collection and preservation for histological analysis. RESULTS: Male groups had significantly higher muscle force production than the female groups at 3 days post injury (p < 0.05). The improvement of maximal force production (p < 0.05) and contraction velocity (p < 0.05) was significant in females only. Histological analysis (necrosis, regeneration, and fibrosis) is ongoing, but preliminary observations concur with the muscle physiology testing that females are recovering faster than males with less fibrosis. CONCLUSIONS: The timeline of the muscle function repair is different between the male and female groups and repair and regeneration continue at 12 days, which suggests interventions can be applied and studied during this time period. Female muscle is recovering faster with less fibrosis. This is likely due to sex-based differences in the interaction of injury severity and inflammation. We are currently examining these mechanistic differences. These results suggest that muscle rehabilitation could benefit from interventions that are sex specific.