Pathological Foundations of Skeletal Muscle After Volumetric Muscle Loss and Targets For Rehabilitation

Abstract Orthopaedic extremity trauma is a major problem resulting in both long-term functional disability and substantial medical cost in various populations. One such injury is volumetric muscle loss (VML), which is clinically identified as a chronic and irrecoverable loss of skeletal muscle tissue resulting in functional impairments. VML is coupled with clinical outcomes related to long-term dysfunction, reduced mobility and physical activity, co-morbidities, and often delayed amputation. Additionally, a major problem identified in the clinic is an inability to respond to rehabilitation; even prolonged and intensive rehabilitation has not been able to ameliorate functional impairments. The fundamental principles of rehabilitation revolve around the plasticity of skeletal muscle, or the ability to adapt to perceived mechanical or chemical cues in order to improve its functional capacity and efficiency. We hypothesize that pathophysiologic limitations in the muscle remaining after VML injury relate to lack of endogenous regenerative ability, such as improvements in whole-body metabolism. We believe that for the VML-injured patient, pathophysiologic changes to the remaining muscle and co-morbidities to injury, such as metabolic inflexibility, could be as much of a problem as the primary loss of contractile tissue. To date, a comprehensive understanding of the natural sequela of injury is absent, specifically, an understanding of the muscle remaining after injury and how the devastating pathophysiologic changes impact the inherent properties of muscle. Our central hypothesis is that muscle dysfunction, muscle fiber and whole-body metabolic insufficiency, and neuromuscular deficiency create a hostile cellular environment in the remaining muscle that mitigates muscle plasticity and blunts the effectiveness of regenerative rehabilitation. We propose three specific aims to address these hypotheses: 1) To establish signaling mechanisms of diminished innervation in the remaining muscle after VML; 2) To identify cellular mechanisms of oxidative adaptation in the remaining muscle after VML; and 3) To determine the contribution of the remaining muscle to whole-body metabolism after VML to improve regenerative rehabilitation. The results of the proposed studies will define cellular mechanisms that contribute to the finite adaptive and regenerative capacity of the remaining muscle after VML and we expect these results could transformative to clinical care for VML-injured patients both acutely and chronically. Additionally, fundamental understanding of the lack of regenerative potential in skeletal muscle could be transformative to other conditions of skeletal muscle such as muscular dystrophies, non-dystrophic myopathies, and sarcopenia.