Metabolic and Contractile Pathophysiology Following Volumetric Muscle Loss Injury

Abstract

Volumetric muscle loss (VML) injury, due to abrupt and significant loss of tissue, exceeds the endogenous regenerative ability of the skeletal muscle, leading to long‐term functional impairment and disability. There is a well‐established physiologic relationship between skeletal muscle mass and metabolism, but the implications of VML injury on this relationship are widely unexplored. Recent investigations have identified oxidative and mitochondrial dysfunction associated with VML injury; however, the local metabolic myofiber response is not completely understood. We hypothesized that significant metabolic and contractile limitations would be observed in the remaining myofibers following VML injury, suggestive of motor unit reorganization. To evaluate the metabolic properties following VML, adult C57BL/6 male mice (n=16) underwent a sham procedure or multi‐muscle full thickness VML injury to the gastrocnemius, soleus, and plantaris muscles (21.1±0.7mg). Two months post‐VML, terminal histologic evaluation of capillarity, mitochondrial content, fibrotic deposition, and myosin heavy chain distribution was completed. Additionally, maximal contractile function and force‐frequency response of the posterior muscle compartment were evaluated. Maximum passive torque at 20 degrees dorsiflexion was significantly greater in the VML group (5.5±0.22 mN·m) compared to sham (2.3±0.13 mN·m). Maximum isometric torque was significantly less in VML (334±28 mN·m) compared to sham (557±66 mN·m). VML injury resulted in slower torque production and elevated twitch:tetani ratio, perhaps indicating a slower muscle fiber phenotype in the tissue remaining. Collectively, this work suggests that motor unit reorganization may alter muscle fiber phenotype following VML injury, likely limiting long‐term muscle functionality.Support or Funding InformationSupported by W81XWH‐18‐1‐0710 & T32AR050938.