Effects of exercise and corticotrophin‐releasing factor 2 receptor agonist on skeletal muscle of mdx mice

Exercise and corticotrophin‐releasing factor 2 receptor (CRF2R) agonist treatment improves skeletal muscle function, however the potential synergistic transcriptional effects of both treatments in dystrophic muscle are not characterized. Mdx (C57BL/10ScSn‐Dmdmdx) and WT (C57BL/6) mice were treated with placebo (PL) or CRF2R agonist and remained sedentary or performed treadmill exercise (EX; 3x/week, 30 minutes at 8–12m/min) for 12 weeks. RNA from tibialis anterior was prepared for gene array analysis using the Affymetrix Mouse 430 array and functional cluster analysis was performed on differentially expressed (DE) genes using DAVID. The Mdx genotype had 224 DE genes, many associated with muscle differentiation and development of the actin cytoskeleton and extracellular matrix. Exercise resulted in 79 DE genes, primarily those involved in transcriptional regulation and circadian rhythms, whereas the CRF2R‐agonist produced 122 DE genes, many involved in chromatin remodeling. The combination of exercise and CRF2R‐agonist resulted in 87 DE genes compared to MDX‐PL‐EX mice, influencing genes involved in protein transport and neuronal nitric oxide synthase (nNOS). These results indicate that the effects of exercise and CRF2R agonist treatment are not identical and that combination treatment may result in a favorable transcriptional signature that holds therapeutic potential. (Funded by P&G)