A high‐fat, high‐sucrose diet exacerbates muscle and metabolic pathology and undermines glucocorticoid efficacy in dystrophin‐deficient mice

Abstract

Duchenne 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. image