Background
Volumetric muscle loss (VML) is a traumatic or surgical orthopaedic injury characterized by a significant loss of skeletal muscle mass and function. Clinically there is no treatment that targets skeletal muscle after VML, and lifelong functional impairments lead to musculoskeletal deformity and comorbidities. While mechanisms driving chronic lack of regeneration remain unclear, pathologic fibrotic deposition and loss of myogenic signaling after injury are thought to be involved. One near-term solution to improve function following VML is to repurpose FDA-approved drugs. This study’s objective was to evaluate effectiveness of an anti-fibrotic, nintedanib, and a hypertrophy stimulant, formoterol combined with leucine, to improve muscle function and regeneration after VML. Muscle function after VML is the key clinical outcome; evaluation of torque thus serves as the main measure of success.

Methods
Adult (12-week-old) male C57BL/6 mice (n=29) underwent unilateral VML surgery removing ~15% of the posterior muscle compartment (gastrocnemius, soleus, plantaris) or remained injury-naïve controls. VML-injured mice were randomized to nintedanib (6mg/kg/day), formoterol (3mg/kg/day) and leucine (24g/kg/day), or no treatment. Six weeks post-VML activity and whole-body metabolism were evaluated. Maximal in vivo muscle torque was evaluated 8 weeks post-VML, and tissue was collected terminally. Data were evaluated using a one-way ANOVA and Tukey post-hoc, with significance at p<0.05.

Results
Twenty-four-hour metabolic rate was ~17% and 8% higher in the formoterol+leucine group (16.5kcal/hour) compared to injury naïve and VML alone, respectively (p<0.001); despite no ambulation or respiratory exchange ratio differences (p≥0.069). However, formoterol+leucine treatment increased lipid oxidation (p=0.005). After 8-weeks, gastrocnemius mass:body mass was reduced for VML alone, but both treatments ameliorated this difference (p=0.004). Maximal in vivo torque was greatest in injury naïve mice (609.6mN•m/kg) and ~41% and 49% lower in VML untreated and nintedanib groups, respectively, while formoterol+leucine mitigated this decline (p=0.012).

Conclusion
Understanding the effects of repurposed FDA-approved medications on functional recovery after VML can establish translational options. Formoterol+leucine treatment improved torque of the posterior muscle compartment and muscle mass to a level not statistically different from injury-naïve mice, supporting its role in promoting functional recovery after VML. This strategy warrants further research to consider applications for VML-injured patients.

Orthopaedic Surgery - Drug Therapies after Volumetric Muscle Loss Injury: Recovery of Function and Muscle Mass with Formoterol - Orthopaedic Surgery

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Orthopaedic Surgery - Drug Therapies after Volumetric Muscle Loss Injury: Recovery of Function and Muscle Mass with Formoterol - Orthopaedic Surgery

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