The prevalence of cardiomyopathy from metabolic stress has increased dramatically; however, its molecular mechanisms remain elusive. By screening obese/diabetic animal models, here we reveal that extracellular signal-regulated protein kinase 5 (Erk5) is lost selectively in their hearts. Cardiacspecific
deletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractility
andmitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). We further show that Erk5 regulation of peroxisome proliferator-activated receptor γ coactivator- 1α (Pgc-1α) is critical for cardiac mitochondrial functions. More specifically, we show that gp91phox activation of calpain-1 degrades Erk5 in free fatty acid (FFA)-stressed cardiomyocytes, whereas the prevention of Erk5 loss by blocking gp91phox or calpain-1 rescues mitochondrial functions. Similarly, adeno-associated virus 9 (AAV9)-mediated restoration of Erk5 expression in Erk5-CKO hearts prevents cardiomyopathy. These findings suggest that maintaining Erk5 integrity
has therapeutic potential for treating metabolic stress-induced cardiomyopathy.