["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend A high‐fat, high‐sucrose diet (HFHSD) exacerbated muscle and metabolic dysregulation in mdx mice while also altering the physiological response to prednisolone (Pred) In diaphragms of control diet (CD)‐fed mdx mice, prednisolone treatment improved muscle function and reduced fibrosis, inflammatory signalling, and mitochondrial dysregulation, although fatty infiltration increased compared to untreated CD‐fed mdx (grey arrows). In contrast, the HFHSD increased body fat, glucose intolerance, insulin resistance (IR), fatty infiltration, and mitochondrial dysregulation while also reducing muscle function, fibrosis, and inflammatory signalling compared to untreated CD‐fed mdx mice (red arrows). Importantly, the HFHSD attenuated or prevented several beneficial effects of Pred, including improvements in muscle function and mitochondrial regulation. In some cases, the combination of the HFHSD and Pred further exacerbated pathology beyond the HFHSD alone, including glucose intolerance and IR. For HFHSD‐Pred, black arrows indicate comparison to untreated CD‐fed mdx, whereas red arrows indicate greater magnitude of change compared to untreated HFHSD‐fed mdx mice. Figure created with Biorender.com.\n\n\n\n\n\n\n\n\n\nAbstract\nDuchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by dystrophin deficiency and characterized by progressive muscle wasting. DMD is frequently accompanied by obesity and insulin resistance (IR); however, their influence on disease progression remains unknown. Moreover, the extent to which these comorbidities may interact with glucocorticoids, a commonly used intervention, is also unknown. We hypothesized that a high‐fat, high‐sucrose diet (HFHSD) would cause IR and accelerate disease progression, and treatment with prednisolone (Pred) would mitigate these effects. To test this hypothesis, 6‐week‐old C57 and mdx mice were fed a control diet (CD) or a HFHSD for 19 weeks, with or without Pred. In C57 and mdx mice, the HFHSD increased body fat percentage and caused hyperglycaemia, glucose intolerance and IR, and, in mdx mice, Pred exacerbated HFHSD‐mediated hyperglycaemia, glucose intolerance and IR. The HFHSD augmented diaphragm fatigue and blunted the beneficial effects of Pred on specific tension in mdx mice. In C57 and mdx mice, the HFHSD increased fatty infiltration in diaphragm, but trichrome staining revealed the HFHSD and/or Pred decreased disease‐related fibrosis in mdx mice. Additionally, the HFHSD altered disease and/or Pred‐mediated changes to proteins associated with lipid storage, inflammatory signalling, mitochondrial/metabolic regulation, and Sestrin signalling. These data indicate that in mdx mice, 19 weeks of a HFHSD independently impaired muscle function, altered muscle composition, and further compromised muscle cell health, and that its interaction with Pred prevented functional recovery and further exacerbated glycaemic dysregulation and cellular dysfunction.\n\n\n\n\n\n\n\n\n\nKey points\n\nObesity and insulin resistance (IR) are common comorbidities of Duchenne muscular dystrophy (DMD), yet their influence on dystrophic pathology remains unknown. Additionally, the extent that obesity/IR interact with glucocorticoids in dystrophic progression is unclear.\nTo address this, mdx mice were fed a high‐fat, high‐sucrose diet (HFHSD) for 6 months, with and without glucocorticoid treatment, and outcomes related to muscle function, composition, and cell health were evaluated.\nA HFHSD decreased fatigue resistance, reduced fibrosis, increased fatty infiltration, and impaired cell health in dystrophic diaphragms.\nThe addition of glucocorticoids to the HFHSD did not considerably improve most outcomes, suggesting that the diet may blunt some glucocorticoid‐mediated benefits, but did increase specific tension, reduce fibrosis, and attenuate inflammatory signalling.\nThese results demonstrate that a HFHSD impacts some parameters of dystrophic physiology and highlight the importance of considering systematic and muscle metabolism when implementing therapeutic strategies.\n\n\n"]