Running-based rehabilitation does not improve muscle function after volumetric muscle loss despite improving hindlimb weight-bearing asymmetry in mice.

Volumetric muscle loss (VML) is a traumatic skeletal muscle injury characterized by chronic functional impairments in the affected muscle and adjacent uninjured bone. Rehabilitative strategies aimed at restoring limb function following VML, including voluntary running, have shown limited efficacy and in some cases have been detrimental. One potential explanation is disproportional loading of the uninjured contralateral limb during running, but evaluation of unilateral weight-bearing following VML has not been explored. This study was designed to evaluate if the limited response to rehabilitation following VML could be explained by limb loading asymmetry. Twelve-week-old C57Bl/6J mice (n = 24; equal males/females) were randomized to three groups: Naïve-Run, VML, and VML-Run. Two weeks post-VML, mice in running groups were provided free access to wheels for 6 weeks. Weight-bearing asymmetry was assessed before injury and biweekly thereafter. Terminally at ∼20 weeks of age, in vivo muscle function was evaluated, and muscles and bones were saved for analyses. Prior to injury, no difference in weight-bearing asymmetry was observed across groups. VML-injured mice exhibited similar weight-bearing asymmetries prior to running. Following 6 weeks of running, VML-Run mice regained weight-bearing symmetry comparable to Naïve-Run. Despite this, remaining muscle function remained persistently impaired following VML injury. Collectively this works suggests that voluntary running promotes favourable weight-bearing adaptations following VML, but does not improve muscle function or the mechanical properties of the adjacent bone.