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

Abstract

Recent studies have shown that administration of peroxisome proliferator-activated receptor-beta (PPARbeta) agonists enhances fatty acid oxidation in rodent and human skeletal muscle and that muscle-restricted PPARbeta overexpression affects muscle metabolic profile by increasing oxidative myofiber number, which raises the possibility that PPARbeta agonists alter muscle morphology in adult animals. This possibility was examined in this study in which adult mice were treated with a PPARbeta 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 PPARbeta activation is associated with a calcineurin-dependent effect on muscle morphology that enhances the oxidative phenotype.

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

“…Pharmacological activation of the muscle-specific PPAR␤/␦ isoform promotes muscle development, myonuclear accretion, and satellite cell proliferation and restores sarcolemmal integrity in dystrophic mice models (17,19,23,50,51), strongly supporting a role for PPAR␤/␦ in regulating postnatal muscle growth and development. However, no study has yet clearly revealed the molecular mechanism(s) through which PPAR␤/␦ regulates skeletal muscle growth.…”

Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ

“…These include, for example, the phosphatase calcineurin (Chin et al, 1998;McCullagh et al, 2004). However, pharmacological inhibition of cal-PPAR␦ IN SKELETAL MUSCLE cineurin by cyclosporin A results in impaired PPAR␦-mediated induction of changes in myofiber metabolic phenotype (Gaudel et al, 2008), indicating a cross-talk between these different pathways. Finally, it is worth remembering that significant differences exist between rodent and human skeletal muscle with regard to fibertype homogeneity/regulation and degree of skeletal muscle fiber-type transformation (Holloszy and Coyle, 1984;Delp and Duan, 1996).…”

“…In addition to enhancing expression of genes required for lipid oxidation and myogenic markers, pharmacological activation of PPAR␦ in adult mice has recently been linked to a rapid and transient up-regulation of angiogenic markers (VEGF-A and PECAM-1) (Gaudel et al, 2008). In a mouse ischemic hind limb model, PPAR␦ agonist treatment resulted in improved vasculogenesis via regulation of endothelial progenitor cells, highlighting the potential for PPAR␦ agonism as a novel option for treatment of ischemic cardiovascular diseases .…”

“…Because the L-165041 is only a weak agonist of the murine PPAR␦, other more potent PPAR␦ ligands were developed (Willson et al, 2000). Use of the potent and high-affinity synthetic PPAR␦ ligands in different animal models and in human studies showed that activation of PPAR␦ can promote reversal of metabolic abnormalities (Oliver et al, 2001;Jucker et al, 2007;Chen et al, 2008;Gaudel et al, 2008;Risérus et al, 2008;Kleiner et al, 2009). The diet-induced obesity that mice fed a high-fat diet develop could be prevented by treatment with GW501516 because of enhanced fatty acid utilization and energy expenditure (Tanaka et al, 2003).…”

Peroxisome proliferator-activated receptors as stimulants of angiogenesis in cardiovascular disease and diabetes

“…26 Gaudel et al showed that PPAR-β/δ activation resulted in a 1.5-fold increase in capillary number in mouse skeletal muscle. 27 In a study of tissue samples obtained from human colorectal carcinomas and matched adjacent tissues, VEGF expression, microvascular density, and venous vessel invasion increased as the expression of PPAR-β/δ and cyclooxygenase (COX)-2 increased. 28 He et al performed a set of experiments in human endothelial progenitor cells (EPCs) which showed that impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by treatment with a PPAR-β/δ agonist.…”