Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease that results from a lack of functional dystrophin protein and is commonly treated with glucocorticoids. Obesity and insulin resistance (IR) are frequently observed in DMD patients; however, their impact, with and without glucocorticoids, on dystrophic progression and lipid metabolism remains poorly defined. We hypothesized that a high-fat, high-sucrose diet (HFHSD) would worsen DMD-induced lipid dysregulation and that prednisolone (Pred) treatment would further intensify these alterations. To test this, 6-week-old male C57 and mdx mice were fed a control diet (CD) or a HFHSD for 18 weeks, with or without Pred, and the diaphragm was collected for subsequent analyses. The HFHSD increased body fat percentage in both C57 and mdx mice compared to respective CD-fed mice (p< 0.01). Using oil red O staining, we discovered the HFHSD increased fatty infiltration in C57 and mdx mice compared to respective CD-fed mice (p< 0.01-0.05), and Pred increased fatty infiltration in mdx mice fed the CD (p< 0.05). Further, the HFHSD increased lipid droplet size in mdx mice (p< 0.05), but size was not impacted by Pred. To better understand systemic changes in lipid metabolism, we performed a lipidomic analysis on blood. Dystrophin deficiency caused broad lipid dysregulation, such that 233 lipid species were significantly increased and 3 were significantly decreased in mdx-CD compared to C57-CD (FDR< 0.1). Increased lipid species indicated impaired fatty acid oxidation, altered phospholipid metabolism and biosynthesis, and elevated ceramides, suggesting membrane destabilization and turnover, as well as enhanced inflammatory ceramide production. Within mdx mice, the HFHSD further dysregulated lipid metabolism, increasing 137 additional lipid species and decreasing 43 additional lipid species in mdx-HFHSD compared to mdx-CD (FDR < 0.1), reflecting enhanced sphingolipid biosynthesis, phospholipid remodeling, and glycerolipid metabolism, and suggesting a shift toward increased lipid storage and stress-associated lipid signaling. Within mdx mice fed the HFHSD, Pred further intensified lipid metabolism dysregulation, as an additional 49 lipid species were increased and 3 decreased (FDR< 0.1) in mdx-HFHSD-Pred compared to mdx-HFHSD-no Pred. These increased species were associated with phospholipid metabolism, sphingolipid biosynthesis, fatty acid and glycerolipid metabolism, and fatty acid elongation, indicating increased lipid storage, intensified glycerolipid turnover, and altered mitochondrial membrane lipid dynamics. Collectively, these data demonstrate that dystrophin deficiency profoundly disrupts lipid metabolism, and this is further exacerbated by a HFHSD and intensified by Pred. These findings highlight the complex, multisystemic and metabolic consequences of dystrophin deficiency and underscore the urgent need to integrate metabolic management into the care of individuals with DMD. This research was supported by MDA grant #962344. This abstract was presented at the American Physiology Summit 2026 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.
Vorwald et al. (Fri,) studied this question.