Volumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e. oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1 overexpression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle adaptive capacity and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.Oxidative capacity is a cornerstone of skeletal muscle health, and for the past 40 years, we have known that the most robust physiologic adaptation to regularly scheduled physical activity (i.e., exercise/overload training) is an increase in oxidative capacity (1,2). Improvements in muscle oxidative capacity are made possible with exercise training through adaptations affecting the density and function of the intramuscular mitochondrial network. The signaling pathways that initiate and coordinate mitochondrial improvements with exercise are complex, but advancements in molecular biology in the last two decades have revealed many of the key players involved (see for review (3)). Most notably, the transcription factor PGC-1 (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) is considered a critical molecular modulator of skeletal muscle oxidative plasticity because it regulates gene expression patterns for expansion of the mitochondrial network (i.e. mitochondrial biogenesis), angiogenesis, and motor neuron associated adaptations with exercise training(4-6). Expansion of the vasculature and mitochondrial network with exercise training enhances the functional capacity of the muscle (e.g., fatigue resistance), and in general, this physiologic type of acclimation is considered beneficial for human performance and health (7,8).Large-scale skeletal muscle trauma, such as volumetric muscle loss (VML) injury, is unique in that the muscle is not able to regenerate muscle fibers with endogenous repair systems and as a result, cannot fully recover strength. The loss of muscle function (i.e., contractility) can exceed the loss of tissue mass(9), and this permanent functional deficit leaves patients with lifelong disability(10) for which there is currently no corrective physical rehabilitation guidelines. Furthermore, the extent to which the remaining skeletal muscle can adapt to rehabilitation is unclear. Recent preclinical work has investigated various...