Physical inactivity following volumetric muscle loss results in a divergence between whole-body and cellular metabolic dysfunction

Abstract

Volumetric muscle loss (VML) is the frank loss of muscle due to injury or surgery and is characterized by whole-body and cellular metabolic dysfunction. Following VML, prolonged bedrest and life-long disability may worsen metabolic dysfunction. This work aimed to elucidate the impact of VML and physical inactivity on the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle. Adult male C57BI/6J mice (n=40) underwent unilateral VML to the posterior hindlimb compartment or served as age-matched injury naïve controls, then were randomized to standard or restricted activity cages for 8-wks. Physical activity, whole-body metabolism, and glucose tolerance were evaluated at 6- and 7-wks post-VML, respectively. Small molecule metabolites and lipids were measured using liquid chromatography-couple and flow injection tandem mass spectrometry. Differences were evaluated by two-way ANOVA with Tukey’s HSD post hoc. Inactivity following VML resulted in ~7% decrease in 24-hr metabolic rate compared to VML alone (p=0.032). Regardless of injury, 24-hr RER was ~5% greater following inactivity (p=0.001). Over 24 hrs, carbohydrate oxidation was ~23% greater with injury and inactivity (p=0.001); lipid oxidation was largely unchanged (p≥0.068). Change in RER (ΔRER) was ~93% greater in VML-injured mice (p=0.030). Physical activity can influence whole-body metabolism, and inactivity post-VML results in greater whole-body carbohydrate usage. Regardless of activity, blood glucose levels were lower following injury (p<0.001). Adiponectin was greater in VML-injured muscles (p<0.001), which may explain enhanced whole-body glucose tolerance post-VML. Protein expression of localized metabolic signals revealed muscle GLUT4, fatty acid binding protein 4, acetyl-CoA carboxylase (ACC), phosphorylated ACC (pACC) and liver fatty acid synthase (FAS) were unaffected by injury and inactivity (p≥0.117). Muscles of inactive, VML-injured mice exhibited a greater pACC:ACC ratio (p=0.046), suggesting decreased fatty acid synthesis. No effect of injury or inactivity was observed in circulating leptin (p≥0.188). Beta-hydroxyacyl CoA dehydrogenase activity was decreased following injury, suggesting a diminished capacity to oxidize fatty acids (p=0.033). Inactivity alone did not alter the metabolome. Injury resulted in 54 significantly expressed metabolites and/or ratios. The combination of injury and inactivity produced a similar response as VML alone, with 91% of metabolites and/or ratios commonly expressed between groups. Similar metabolite expressions following VML with and without inactivity indicate VML injury alone is regulating an altered metabolome. Collectively, although there was no substantial impact of inactivity on whole-body metabolic dysfunction above VML alone, metabolic changes in VML-injured muscles suggests functional alterations in fatty acid metabolism with inactivity. If the ability to oxidize fatty acids is exhausted following VML, resulting accumulation of triglycerides may contribute to metabolic disease often observed with physical inactivity. Continued work to elucidate mechanisms and functional aspects of fatty acid oxidation following VML is needed. W81XWH-20-1-0885 and R01-AR078903 to JAC & SMG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.