Aerobic Exercise Training Does Not Attenuate Fibrosis In Autologous Repaired Vml-injured Skeletal Muscle

Traumatic loss of skeletal muscle with irrecoverable loss of muscle function, volumetric muscle loss (VML), commonly occurs in civilian and military populations suffering severe extremity trauma and is associated with pathological fibrosis which reduces overall muscle force production. While current treatments for volumetric muscle loss (VML) remain insufficient, combined therapeutic approaches—such as autologous muscle grafts paired with exercise—have shown promising results in enhancing the rate of force recovery. Previous findings by our laboratory demonstrated accelerated force recovery following exercise in VML-injured male rats, however the exact etiology of that improvement remains elusive. PURPOSE: Evaluate the efficacy of exercise as a combinatory treatment with autologous muscle grafts on markers of muscle fibrosis in VML injured male rats. METHODS: 32 male Sprague-Dawley rats had ~20% of their left tibialis anterior (LTA) removed then replaced to act as an autologous repair with the right tibialis anterior (RTA) serving as the contralateral control. Half of the rats engaged in exercise through wheel running, while the other half served as non-exercise controls. TAs were excised at 2 and 8 weeks post-VML for morphological and gene expression analyses. RESULTS: The percentage of noncontractile tissue (%NCT) was ~5% in the RTA independent of exercise. However, %NCT was ~40% in the LTA at 2 weeks post-VML and ~ 27% at 8 weeks post-VML independent of exercise (p < 0.05). The VML group had higher Tgfb (~11.4-fold; P < 0.05), Col1a2 (~37.3-fold; P < 0.05), Col3a1 (~24.8-fold; P < 0.05), and Mmp2 (~19.6 -fold; P < 0.05) mRNA abundance 2-weeks post-VML independent of exercise. The VML group had higher Tgfb (~3.4-fold; P < 0.05), Col1a2 (~13.1-fold; P < 0.05), Col3a1 (~24.8-fold; P < 0.05), and Mmp2 (~2.8-fold; P < 0.05) mRNA abundance 8-weeks post-VML independent of exercise. CONCLUSION: Our data demonstrate the combinatory treatment of exercise with autologous muscle grafts is insufficient to mitigate fibrotic development in VML, indicating reductions in fibrosis may not be responsible for accelerated muscle force recovery following exercise. Further research is required to evaluate potential mechanisms of accelerated muscle force recovery with autologous repair and exercise in VML. Supported by: R15AR064481; Arkansas Biosciences Institute