Aberrant mechanical-metabolic coupling in muscular dystrophy: gene expression and functional studies in mdx mouse muscle in relation to age and exercise

Weakness and fatigability, typical features of Duchenne muscular dystrophy, are aggravated in mdx mice by a chronic exercise on horizontal treadmill (30 min running at 12 m/min twice a week). This protocol leads to a significant decrease in limb force vs. non exercised mdx mice by grip test; preliminary results by torque recordings confirm this functional impairment. Parallel ex vivo studies show that the exercise increases the resistance to eccentric contraction in C57BL/10 wildtype (wt) extensor digitorum longus (EDL) muscles, while such an adaptation is not observed in mdx ones, which remain weaker than controls. In order to understand the molecular mechanisms underlying exercise susceptibility of mdx mice we investigated by quantitive realtime PCR the outcome of 4 (T4, 8 weeks of age) and 12 (T12; 16 weeks of age) weeks of either exercise or cage-based activity on a large set of genes in gastrocnemius muscle of mdx and wt mice. Basal expression of peroxisome proliferator receptor γ coactivator 1α (PGC1α) and sirtuin1 is higher in mdx vs. wt at both ages. Exercise increases PGC1α expression in wt, while in mdx mice T12 exercise down-regulates PGC1α, sirtuin1, PPARγ and the autophagy marker BNIP3. 16 week-old mdx mice show a basal overexpression of the slow phenotype genes; T12 exercise fully contrasts this basal adaptation and the high expression of follistatin and myogenin, being ineffective in wt mice. Damage and inflammation related genes, such as NADPHoxidase, TGFβ and TNFα are overexpressed in mdx muscle in all conditions. In parallel the anti-inflammatory adiponectin is lower in T12 exercised mdx muscle. Then a chronic exercise with minor adaptive effects in wt muscle, contrasts compensatory changes in the benign mdx phenotype leading to a disequilibrium between protective and damaging signals and disclosing potential drug targets (Supported by NLDDP and Italian MIUR-PRIN project n. 20108YB5W3_004).