Abstract: Localized skeletal muscle injury (e.g., volumetric muscle loss; VML) can disrupt diurnal metabolic flexibility. However, it remains unclear how the evaluation of whole-body metabolism and physical activity following a prandial stimuli may reveal differences in metabolic flexibility between injured and uninjured states. This study aimed to develop a novel tool to examine whole-body metabolic impairments following VML injury, with consideration of lipid-related mechanisms. Adult C57Bl/6J mice (n=50; equal males and females) were randomized to a methodology development cohort; to undergo VML injury, intramuscular glycerol injection, or remain injury naïve controls. The developed tool using an i.p. glucose injection and indirect calorimetry was used to characterize the dynamic nature of whole-body metabolism. Whole-body metabolism, in vivo muscle function, and markers of lipid and glycemic regulation were evaluated 6 weeks following injury. Females, regardless of injury, exhibited greater daily energy expenditure alongside increases in activity. Females exhibit lower whole-body lipid oxidation during the inactive period, despite higher in active period, suggesting more coordinated substrate utilization. Biologic sex differences in post-prandial substrate utilization, reveal males fail to suppress whole-body lipid oxidation; exhibiting marked impairments in post-prandial metabolic flexibility. VML injury increases protein expression of perilipin 2 and SIRT1 in the muscle remaining. While inducing sex-specific changes, with ATGL expression markedly increased and perilipin 5 expression is reduced in females. The remaining muscle following VML accumulates neutral lipids and perilipin 1-positive adipocytes. This work highlights sex-specific mechanisms of metabolic disruption following traumatic skeletal muscle injuries, such as VML.
Bruzina et al. (Wed,) studied this question.