Acute and chronic effects of exercise on mRNA expression in the skeletal muscle of two mouse models of peripheral artery disease.

Endurance exercise improves walking performance in patients with peripheral artery disease (PAD), which is characterized by skeletal muscle dysfunction caused by lower extremity ischemia. Although transcriptional analyses of exercise-induced changes in normal animals and healthy volunteers have been reported, no detailed study has explored exercise-induced alterations in gene expression in PAD animal models. Here, we determined the acute and chronic effects of exercise on mRNA expression in the skeletal muscles of two mouse models of PAD. Three particular gene categories were investigated: known exercise-responsive genes (Pgc1a, Il6, Nr4a1, Nr4a2, and Nr4a3); myogenic and muscle regeneration-related genes (Myf5, Myogenin, Myomaker, and Myh3); and Gpr56 and its ligand Col3a1. PAD was induced by bilateral femoral artery ligation in normal C57BL/6 and diabetic KK-Ay mice. From 1 week after surgery, repetitive twice-weekly 30-min treadmill endurance exercise sessions were applied. Altered mRNA expression in the soleus muscles was measured in both the acute and chronic phases. In the acute phase, transcript levels of exercise-inducible genes showed significant increases in both C57BL/6 and diabetic KK-Ay PAD mice; levels of regeneration-related genes showed little alteration, and those of Gpr56 increased immediately and significantly after exercise in both models. In the chronic phase, transcript levels of Pgc1a, Myf5, Myogenin, Myomaker, Myh3, Gpr56, and Col3a1 were upregulated significantly in sedentary C57BL/6 PAD mice compared with that in sham-operated mice. Exercise training inhibited the upregulation of Col3a1, Myf5, and Myogenin significantly. In KK-Ay PAD mice, only Gpr56 mRNA levels increased significantly compared with those in sham-operated mice. RNA sequence analysis revealed 33 and 166 differentially upregulated, and 363 and 99 downregulated, genes after exercise training in C57BL/6 PAD and KK-Ay PAD mice, respectively. In summary, we detected significant alterations of skeletal muscle genes after exercise in PAD mouse models and characterized their expression patterns.