Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction.

Following traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in 5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar (91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequala of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.