Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism.

Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathologic comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β 2 receptor agonists (e.g., formoterol) improves metabolic and skeletal muscle function. We first aimed to examine if restricting physical activity following injury affects metabolic and skeletal muscle function. Second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24-hr physical activity and whole-body metabolism evaluations were conducted post-VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity, and untargeted metabolomics. Restricting activity chronically post-VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate post-VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. KEY POINTS: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modeling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and to enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury. Abstract Figure. This study evaluated the effects of physical activity restriction and treatment with a β 2 adrenergic receptor agonist, formoterol, on whole-body and local muscle metabolism function 8 weeks following volumetric muscle loss (VML) injury. Physical activity restriction decreased ambulation and metabolic rate while increasing the respiratory exchange ratio (RER), an indication of the diurnal use of substrates used as fuel, due to decreased lipid oxidation. In contrast, formoterol treatment increased injured muscle mass and function while improving glucose uptake and metabolic flexibility, the ability to transition efficiently between fuels over the course of the day. Neither treatment or activity restriction affected markers related to atrophy (MuRF1, Atrogin-1), hypertrophy (Akt), or regulators of mitochondrial biogenesis (PGC-1α). This article is protected by copyright. All rights reserved.