PPARd activation improves cardiac mitochondrial homeostasis in desmin deficient mice but does not alleviate systolic dysfunction

Peroxisome proliferator-activated receptor (PPAR) d is a major transcriptional regulator of cardiac energy metabolism with pleiotropic properties, including anti-inflammatory, anti-oxidative and cardioprotective action. In this study, we sought to investigate whether pharmacological activation of PPARd via intraperitoneal administration of the selective ligand GW0742 could ameliorate heart failure and mitochondrial dysfunction that have been previously reported in a characterized genetic model of heart failure, the desmin null mice (Des(-/-)). Our studies demonstrate that treatment of Des(-/-) mice with the PPARd agonist attenuated cardiac inflammation, fibrosis and cardiac remodeling. In addition, PPARd activation alleviated oxidative stress in the failing myocardium as evidenced by decreased ROS levels. Importantly, PPARd activation stimulated mitochondrial biogenesis, prevented mitochondrial and sarcoplasmic reticulum vacuolar degeneration and improved the mitochondrial intracellular distribution. Finally, PPARd activation alleviated the mitochondrial respiratory dysfunction, prevented energy depletion and alleviated excessive autophagy and mitophagy in Des(-/-) hearts. Nevertheless, improvement of all these parameters did not suffice to overcome the significant structural deficiencies that desmin deletion incurs in cardiomyocytes and cardiac function did not improve significantly. In conclusion, pharmacological PPARd activation in Des(-/-) hearts exerts protective effects during myocardial degeneration and heart failure by preserving the function and quality of the mitochondrial network. These findings implicate PPARd agonists as a supplemental constituent of heart failure medications.