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.

Grant Number: 5R01AR078903-04
NIH Institute/Center: NIH
Principal Investigator: Jarrod Call