Pharmacological activation of PPAR{beta} promotes rapid and calcineurin-dependent fiber remodeling and angiogenesis in mouse skeletal muscle

1 Institut National de la Santé et de la Recherche Médicale U907 and Université de Nice-Sophia Antipolis, Faculté de Médecine, Nice, France; and 2 Department of Medicine, Washington University, St. Louis, Minnesota Submitted 7 September 2007 ; accepted in final form 19 May 2008 Recent studies have shown that administration of peroxisome proliferator-activated receptor-β (PPARβ) agonists enhances fatty acid oxidation in rodent and human skeletal muscle and that muscle-restricted PPARβ overexpression affects muscle metabolic profile by increasing oxidative myofiber number, which raises the possibility that PPARβ agonists alter muscle morphology in adult animals. This possibility was examined in this study in which adult mice were treated with a PPARβ 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 PPARβ activation is associated with a calcineurin-dependent effect on muscle morphology that enhances the oxidative phenotype. myogenesis; metabolism; Type 2 diabetes Address for reprint requests and other correspondence: P. A. Grimaldi, Inserm U907, Faculté de Médecine Université de Nice-Sophia Antipolis, 28 Ave. de Valombrose, Nice F-06107 Cedex, France (e-mail: grimaldi{at}unice.fr )