METABOLOMIC PROFILING REVEALS DISTINCT METABOLIC SIGNATURES ASSOCIATED WITH DIFFERENTIAL SKELETAL MUSCLE SUSCEPTIBILITY IN MDX MICE MODEL

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle degeneration, although individual muscles exhibit strikingly different susceptibilities to disease progression. While the diaphragm undergoes severe degeneration early in life, the tongue remains relatively resistant despite the shared absence of dystrophin, suggesting the existence of intrinsic protective mechanisms. We hypothesized that distinct metabolic adaptations underlie these divergent phenotypes and therefore performed a comparative ¹H nuclear magnetic resonance (NMR)-based metabolomic analysis of diaphragm and tongue tissues from young and aged wild-type and mdx mice. Metabolite identification and quantification were performed using MetaboLabPy. Principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and pathway enrichment analyses were subsequently conducted in MetaboAnalyst. Metabolomic profiling revealed clear tissue-specific signatures that distinguished both muscle type and disease stage, indicating distinct patterns of metabolic remodeling during DMD progression. In the diaphragm, dystrophin deficiency was associated with marked alterations in the TCA cycle, glycolysis, amino acid metabolism, redox homeostasis, and purine metabolism, reflected by changes in metabolites including taurine, myo-inositol, and creatine, consistent with progressive metabolic dysfunction accompanying chronic muscle degeneration. In contrast, the tongue displayed comparatively limited metabolic perturbations despite dystrophin deficiency, suggesting the preservation of adaptive metabolic programs associated with its relative resistance to disease. These findings indicate that muscle-specific metabolic remodeling extends beyond the primary genetic defect and may contribute to the differential vulnerability of skeletal muscles in DMD. By identifying metabolic pathways associated with natural muscle resistance, this study provides new insights into the biological mechanisms underlying disease progression and supports muscle metabolism as a promising target for future therapeutic investigation.