Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signalling

Wei Liu, Andrea Ruiz Velasco Hernandez, Shoubao Wang, Saba Khan, Min Zi, Andreas Jungmann, Maria Dolores Camacho-Munoz, Jing Guo, Guanhua Du, Liping Xie, Delvac Oceandy, Anna Nicolaou, Gina Galli, Oliver J. Müller, Elizabeth Cartwright, Yong Ji, Xin Wang

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number494
JournalNature Communications
Early online date8 Sept 2017
Publication statusPublished - 8 Sept 2017


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