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.