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

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

doi:10.1038/s41467-017-00664-8

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.

Highlights

The prevalence of cardiomyopathy from metabolic stress has increased dramatically; its molecular mechanisms remain elusive
Acting as the primary ATP suppliers and oxygen consumers, mitochondria exert their functions under exquisitely controlled gene regulation circuits, which work through a set of the nuclear receptor superfamily, including the peroxisome proliferator-activated receptors (Ppars), estrogen-related receptors (Errs) and nuclear respiratory factors (Nrfs), and Pparγ co-activator 1 (Pgc-1α and Pgc-1β)[6]
To evaluate Erk[5] involvement in response to metabolic stress from obesity and diabetes, we first examined Erk[5] expression in various obese and diabetic animal models, such as C57BL/6J mice fed with 25-week high fat diet (HFD), two diabetic mouse models of db/db and ob/ob mice, and Rhesus monkeys with spontaneous metabolic syndrome[12]

Summary

Introduction

The prevalence of cardiomyopathy from metabolic stress has increased dramatically; its molecular mechanisms remain elusive. 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 Erk[5] in mice (Erk5-CKO) leads to dampened cardiac contractility and mitochondrial abnormalities with repressed fuel oxidation and oxidative damage upon high fat diet (HFD). Its C-terminal tail contains a transactivation domain for regulating a number of transcription factors, such as myocyte enhancer factor 2 (Mef2), kruppel-like factor 2/4 (Klf2/4) and cAMP response element-binding protein (Creb)[8, 9] Through these transcription factors, Erk[5] participates in a host of biological events, including cell proliferation, survival, muscle maturation, and inflammatory response[8,9,10,11]. Mechanistic studies revealed that FFA-caused Erk[5] b

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Results

Conclusion