Volumetric muscle loss (VML) refers to the traumatic or surgical loss of skeletal muscle tissue, resulting in permanent functional deficits and long-term disability. Currently, there are no efficacious VML treatments; regenerative repair strategies (e.g., autologous muscle grafts) have shown encouraging yet limited results, failing to achieve complete functional recovery. VML causes dysfunctional muscle regeneration, with sex differences and underlying mechanisms poorly understood. Key processes like ECM remodeling and myogenesis are notably disrupted, making the analysis of these markers crucial for understanding the impairment. Exercise promotes muscle recovery through mitochondrial biogenesis, angiogenesis, and satellite cell activation. Most VML studies use low-intensity exercise, while high-intensity training yields different muscle adaptations that support healing. It is unclear if combining autologous muscle grafts with high-intensity exercise improves muscle fiber regeneration. We hypothesize that combining autologous muscle grafts with high-intensity exercise enhances muscle fiber regeneration by boosting myogenic gene expression and reducing ECM markers. Sprague-Dawley rats underwent surgical removal of ~20% of the left tibialis anterior (LTA), which was replaced with autologous muscle tissue for repair. The right tibialis anterior (RTA), which remained uninjured, served as internal control. Rats were placed on a treadmill at 25-30 m/min for 15 minutes with an incline of 0%. At 12 weeks of post-VML, tissue from the repaired LTA and the RTA was collected for analysis. qRT-PCR was used to measure mRNA abundance of ECM and myogenic markers in LTA and RTA muscles. Two-way ANOVA was used to assess interactions of sex and injury (VML (LTA) vs. uninjured (RTA)) for mRNA abundance, with significance set at (P > 0.05). There was a main effect of sex on Pax7 mRNA abundance, independent of injury, with females exhibiting ~30% lower compared to males (p = 0.0146). There was a main effect of injury, independent of sex, with Pax7 and MyoG mRNA abundance ~54% (P=0.008) and ~80% (P=0.02) higher in the LTA than in the RTA, respectively. There was no difference in MyoD mRNA abundance between groups (P< 0.05). There was a main effect of injury, independent of sex, with Col1 and Tgf-β mRNA abundance ~124% (P=0.002) and ~134% (P=0.001) higher in the LTA than in the RTA, respectively. Col3 mRNA abundance was ~150% higher in the male LTA compared to the male RTA (P=0.005). The male LTA also had ~80% higher Col3 mRNA abundance compared with female LTA (P=0.02). Males show different ECM remodeling and myogenic responses to high-intensity exercise and muscle grafts after VML injury compared to females. Understanding these sex differences is crucial for developing targeted treatments for both sexes. ACKNOWLEDGEMENTS: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) under grant number R15AR083119. 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.
Ahmed et al. (Fri,) studied this question.
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