In Duchenne muscular dystrophy (DMD), the absence of dystrophin causes a complex pathogenetic cascade also involving sarcolemmal fragility and metabolic distress. Increasing evidences in mdx mouse model outline the potential interest of therapeutic strategies to reinforce pathways leading to activation of peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α), a key modulator of oxidative metabolism and mitochondrial biogenesis. Accordingly, we recently found beneficial effects of resveratrol, a PGC-1α activator via sirtuin 1 (Sirt1), in exercised mdx mice. To better understand the basal regulation of this mechano-sensitive metabolic pathway in dystrophic skeletal muscle we performed real-time PCR experiments in gastrocnemius (GC) muscles of mdx mice at different ages. We found slightly higher levels of PGC-1α mRNA in mdx mice of 8weeks of age vs. age-matched C57BL/10 (wt) mice. The increase in PGC-1α became highly significant at 16weeks of age and was paralleled by a 40% rise in Sirt1 mRNA. Focusing on 16weeks of age, we then assessed the gene expression of PPARs since PGC-1α cooperates with members of this receptor family to regulate expression of mitochondrial and β-oxidation enzymes. Interestingly, the expression of PPAR-δ was markedly higher in mdx GC muscle vs. wt one, while PPAR-γ had a comparable expression in the two genotypes. Afterwards the impact of the above changes on phenotype and glycolytic/oxidative metabolism of dystrophic muscle has been evaluated on genes expression of myosin heavy chain (MHC) isoforms. A significant increase of slow-oxidative type I MHC and a decrease of fast-glycolytic IIb MHC were found in mdx GC muscle vs. wt ones. Then a modification of PGC-1α pathway, which likely triggers a protective slow-oxidative myofiber program, naturally occurs in the mdx mouse muscle and may modulate the outcome of physiological stimuli and of pharmacological strategies (Supported by Duchenne Parent Project NL).