Mitochondrial Capacities in an Obesity Model of Duchenne Muscular Dystrophy Are Altered by Glucocorticoids

Duchenne muscular dystrophy (DMD), a fatal genetic disease caused by dystrophin deficiency, is often accompanied by metabolic syndrome and mitochondrial impairment. To test the hypothesis that mitochondrial impairments in DMD are exacerbated with obesity and/or glucocorticoid administration, 8-wk-old male mdx and C57 mice received either a control (CON) or high fat, high sucrose (HFHS) diet supplemented with 10 mg/L prednisolone (PR) or no prednisolone (NP) for 21 wk (8 groups total; n = 10/group). At wk 21, a portion of the costal diaphragm was harvested for analysis of oxidative phosphorylation (P) and electron transfer (E) capacities by high-resolution respirometry and estimation of mitochondrial volume density by citrate synthase (CS) activity. Data were analyzed using mixed linear models in SAS v9.4 with disease status, diet, prednisolone group, and all interactions as fixed effects. Overall, C57 mice had greater mitochondrial volume density, as evidenced by greater CS activity, than mdx ( P < 0.0001). Additionally, PR treated animals had greater CS activity than NP regardless of diet or disease status ( P = 0.0002). C57 mice also had greater integrative (per mg tissue) P with complex I (PCI), maximal P (PCI+II), maximal E (ECI+II), and E supported only by complex II (ECII) than mdx mice ( P < 0.0001). The HFHS diet increased integrative measures in C57 ( P < 0.05) but not in mdx mice, whereas PR increased integrative capacities in mdx ( P < 0.05) but not in C57 mice. Importantly, PR in mdx increased integrative PCI to be similar to C57, but integrative PCI+II, ECI+II, and ECII remained below C57 even with PR treatment ( P < 0.05). In C57, intrinsic (relative to CS activity) PCI, PCI+II, ECI+II, and ECII were greater in HFHS than CON ( P < 0.05) but PR decreased capacities (except ECII; P < 0.05) within HFHS to be similar to CON; PR had no impact on intrinsic capacities in C57 mice receiving the CON diet. The opposite was apparent in mdx mice, in which diet did not impact intrinsic capacities but PR tended to increase intrinsic PCI, PCI+II, and ECI+II compared to NP only when mice received the HFHS diet ( P = 0.1). The contribution of Leak to maximal ECI+II was greater in mdx compared to C57 mice ( P = 0.02), whereas mitochondrial coupling efficiency (ratio of maximal P to maximal E) was greater in C57 than mdx ( P < 0.0001). PR treatment increased coupling efficiency in all groups ( P = 0.03), decreased the contribution of complex I during P to maximal E in C57 mice only ( P = 0.03), and increased the contribution of complex II during E to maximal E only in C57 mice on the CON diet ( P = 0.02). The HFHS diet stimulated an increase in mitochondrial capacities without an accompanied increase in mitochondrial density in C57 mice but not in mdx mice. This increase in capacities in obese C57 mice was offset by PR treatment. Conversely, in mdx mice, PR increased mitochondrial capacities only in HFHS-fed mice, but not CON-fed mice. In total, these data indicate that HFHS-induced increases in mitochondrial capacities in healthy mice are negated by PR treatment, whereas mitochondria in mdx mice are resistant to diet-induced increases but PR may improve mitochondrial function in mdx when paired with a HFHS diet. Muscular Dystrophy Association Award 962344 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.