In Sequence Antifibrotic Treatment and Rehabilitation after Volumetric Muscle Loss Injury

<b>Objective:</b> Mitigation of local pathological fibrotic tissue deposition is a target area of interest for volumetric muscle loss (VML); nintedanib has shown promise for reduction of fibrosis after VML. Herein, studies investigate how in sequence antifibrotic treatment administered immediately after VML and delayed rehabilitation could improve functional recovery after VML. <b>Approach:</b> Adult male C57BL/6 mice (<i>n</i> = 36) were VML injured or naïve and randomly assigned to nintedanib (6 mg/kg/day) for 2 weeks or were left untreated; in addition, mice were given access to a running wheel beginning at 2 weeks until 8 weeks. Terminally, mice underwent maximal <i>in vivo</i> functional testing in addition to quantification of muscle collagen content and fibrotic and myogenic markers. <b>Results:</b> Daily running distances (<i>p</i> = 0.17) were similar across groups, but weekly averages were greatest in the VML antifibrotic group (<i>p</i> < 0.01). As expected, 2 weeks post-VML, all VML-injured mice had lower maximal torque normalized to body and muscle mass than naïve. By 8 weeks, running alone after VML did not recover function, but mice that received the antifibrotic treatment before running, had greater torque than those untreated (<i>p</i> < 0.01), with functional measurements similar to naïve muscle that ran, indicating improved functional recovery. <b>Innovation:</b> The ability to translate current Food and Drug Administration-approved pharmaceuticals, in a repurposing approach, is critical to mitigate the pathophysiologic consequences of VML in support of functional recovery. However, foundational and translational studies are still needed to understand feasibility and efficacy. <b>Conclusions:</b> Early prevention of fibrotic tissue deposition supports improvements in muscle quality and force chronically after VML injury.