Sedentary lifestyle is associated with the metabolic syndrome and promoting the oxidative capability of skeletal muscle has been proposed as a therapeutic approach to counteract metabolic disturbances. In cultured myotubes, overexpression of a nuclear receptor involved in the regulation of muscle development and metabolism (peroxisome proliferator-activated receptor β, or PPARβ ), enhances fatty acid catabolism (1). Muscle-specific overexpression of PPARβ in mice promotes an increase in the number of oxidative myofibers and augments resistance against diet-induced obesity (2, 3). Recently, administration of PPARβ agonists has been reported to improve the metabolic phenotype of obese and insulin-resistant animals (4, 5). This study presents in vivo effects of PPARβ activation on muscle morphology on wild-type mice, and describes the mechanism mediating these effects. Adult C57BL6 mice received daily subcutaneous injections of a PPARβ specific activator, or the calcineurin inhibitor cyclosporine A (CsA) or a combination of both. After different times (from 2 to 96 hours), tibialis anterior muscles were harvested immediately after death and used for histological and molecular analyses. PPARβ activation leads to a muscle remodelling, characterized by increases of oxidative fiber and capillary numbers, and a decrease of fiber diameter, completed within 2 days of treatment. This muscle remodelling is accompanied by a quick and transient upregulation of myogenic and angiogenic markers. Both myogenic and angiogenic responses are dependent upon calcineurin activity as remodelling is completely blocked by CsA administration. In conclusion, these data indicate that PPARβ activation is associated with a calcineurin-dependent effect on muscle morphology, that enhances the oxidative phenotype.