When rehabilitation is not enough, how targeting metabolism can overcome the limited plasticity of skeletal muscle after traumatic injury

There is a category of large‐scale neuromusculoskeletal injuries that result in long‐term functional disabilities, and one such injury is volumetric muscle loss (VML) injury. In addition to the clinical outcomes related to long‐term dysfunction, co‐morbidities and reduced mobility and physical activity, this review addresses several underexplored physiological limitations of VML at both the whole‐body level and within the injured muscle. Our objectives with this review are to provide: (1) critical understanding of the pathophysiological limitations related to VML injury; (2) evidence for emerging treatment options that target the VML‐induced metabolic dysregulation; and (3) early functional data on metabolic treatments as a component of regenerative rehabilitation. We highlight new attempts to intervene in this unique pathophysiology, in addition to current unanswered questions for the field.