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

Wei Liu (), Andrea Ruiz-Velasco, Shoubao Wang, Saba Khan, Min Zi, Andreas Jungmann, Maria Dolores Camacho-Muñoz, Jing Guo, Guanhua Du, Liping Xie, Delvac Oceandy, Anna Nicolaou, Gina Galli, Oliver J. Müller, Elizabeth J. Cartwright, Yong Ji () and Xin Wang ()
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Wei Liu: The University of Manchester
Andrea Ruiz-Velasco: The University of Manchester
Shoubao Wang: The University of Manchester
Saba Khan: The University of Manchester
Min Zi: The University of Manchester
Andreas Jungmann: University Hospital Heidelberg
Maria Dolores Camacho-Muñoz: The University of Manchester
Jing Guo: The University of Manchester
Guanhua Du: Chinese Academy of Medical Sciences & Peking Union Medical College
Liping Xie: Nanjing Medical University
Delvac Oceandy: The University of Manchester
Anna Nicolaou: The University of Manchester
Gina Galli: The University of Manchester
Oliver J. Müller: University Hospital Heidelberg
Elizabeth J. Cartwright: The University of Manchester
Yong Ji: Nanjing Medical University
Xin Wang: The University of Manchester

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract The prevalence of cardiomyopathy from metabolic stress has increased dramatically; however, its molecular mechanisms remain elusive. Here, we show that extracellular signal-regulated protein kinase 5 (Erk5) is lost in the hearts of obese/diabetic animal models and that cardiac-specific deletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractility and mitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). Erk5 regulation of peroxisome proliferator-activated receptor γ co-activator-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.

Date: 2017
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DOI: 10.1038/s41467-017-00664-8

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