Pharmacological activation of PPARβ promotes rapid and calcineurin-dependent fiber remodeling and angiogenesis in mouse skeletal muscle

Recent studies have shown that administration of peroxisome proliferator-activated receptor-beta (PPAR beta) agonists enhances fatty acid oxidation in rodent and human skeletal muscle and that muscle-restricted PPAR beta overexpression affects muscle metabolic profile by increasing oxidative myofiber number, which raises the possibility that PPAR beta agonists alter muscle morphology in adult animals. This possibility was examined in this study in which adult mice were treated with a PPAR beta agonist, and the resulting changes in myofiber metabolic phenotype and angiogenesis were quantified in tibialis anterior muscles. The findings indicate a muscle remodeling that is completed within 2 days and is characterized by a 1.63-fold increase in oxidative fiber number and by a 1.55-fold increase in capillary number. These changes were associated with a quick and transient upregulation of myogenic and angiogenic markers. Both myogenic and angiogenic responses were dependent on the calcineurin pathway, as they were blunted by cyclosporine A administration. In conclusion, the data indicate that PPAR beta activation is associated with a calcineurin-dependent effect on muscle morphology that enhances the oxidative phenotype.