Early Rehabilitation and Volumetric Muscle Loss Injury Adapts the Genetic Response of the Remaining Muscle Mass

Volumetric muscle loss (VML) injuries occur due to orthopaedic trauma or the surgical removal of skeletal muscle and result in debilitating long‐term functional deficits. Current treatment strategies do not promote significant restoration of function; it is possible that limitations to traditional rehabilitation may be related to the attenuated potential of the remaining muscle to adapt following injury. We examined early rehabilitation interventions involving range of motion, muscle stimulation, and pharmacologic targeting to augment mitochondrial capacity (via guanidionpropionic acid) in isolation or combination to understand the capability of the remaining muscle mass to adapt during the acute phase of healing after VML injury. Adult male mice underwent an ~20% multi‐muscle VML injury to the posterior compartment (gastrocnemius, soleus, and plantaris muscle) and were randomized to rehabilitation twice per week beginning 72 hours post‐injury or no treatment. During each 30 minute rehabilitation session, passive muscle torque, a measure of muscle stiffness, was recorded. At 3, 7, and 14 days post‐injury muscles from the injured and contralateral limb were harvested and used to quantify the fibrotic, myogenic, inflammatory, and mitochondrial gene expression. The response to VML injury and associated early rehabilitation appeared to be transient over days post‐injury. VML injury without rehabilitation was associated with a large initial increase in inflammatory gene expression at 3 days, which later decreased at 7 days and then increased again at 14 days post‐ injury. The myogenic gene response was initially increased at 3 days but then declined at both 7 and 14 days. Combined rehabilitation increased the acute myogenic response and suppressed the inflammatory response post‐injury. Under normal circumstances, mitochondrial biogenesis accompanies myogenic muscle recovery from injury and is likely to meet the energy demands of muscle repair. Mitochondrial genes were downregulated across all measured time points post‐ injury when left untreated; suggesting mitochondrial dysfunction following injury, with a combined rehabilitation approach this downregulation appears to be blunted. Collectively, early rehabilitation appears to mitigate the acute maladaptive response to VML injury. Additional work is needed to determine if long‐term functional gains can be accomplished by implementing early rehabilitation. Support or Funding Information Studies funded by the Alliance for Regenerative Rehabilitation Research and Training Grant supported by the NICHD, NINDS, and NIBIB.