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

doi:10.1038/s41467-017-00664-8

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 journal › Article › peer-review

Abstract

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 language	English
Article number	494
Journal	Nature Communications
Volume	8
Early online date	8 Sept 2017
DOIs	https://doi.org/10.1038/s41467-017-00664-8
Publication status	Published - 8 Sept 2017

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Liu, W., Ruiz Velasco Hernandez, A., Wang, S., Khan, S., Zi, M., Jungmann, A., Camacho-Munoz, M. D., Guo, J., Du, G., Xie, L., Oceandy, D., Nicolaou, A., Galli, G., Müller, O. J., Cartwright, E., Ji, Y., & Wang, X. (2017). Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signalling. Nature Communications, 8, Article 494. https://doi.org/10.1038/s41467-017-00664-8

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title = "Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signalling",

abstract = "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. Cardiacspecificdeletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractilityandmitochondrial 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 integrityhas therapeutic potential for treating metabolic stress-induced cardiomyopathy.",

author = "Wei Liu and {Ruiz Velasco Hernandez}, Andrea and Shoubao Wang and Saba Khan and Min Zi and Andreas Jungmann and Camacho-Munoz, {Maria Dolores} and Jing Guo and Guanhua Du and Liping Xie and Delvac Oceandy and Anna Nicolaou and Gina Galli and M{\"u}ller, {Oliver J.} and Elizabeth Cartwright and Yong Ji and Xin Wang",

year = "2017",

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doi = "10.1038/s41467-017-00664-8",

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Liu, W, Ruiz Velasco Hernandez, A, Wang, S, Khan, S, Zi, M, Jungmann, A, Camacho-Munoz, MD, Guo, J, Du, G, Xie, L, Oceandy, D , Nicolaou, A , Galli, G, Müller, OJ, Cartwright, E, Ji, Y & Wang, X 2017, 'Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signalling', Nature Communications, vol. 8, 494. https://doi.org/10.1038/s41467-017-00664-8

TY - JOUR

T1 - Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signalling

AU - Liu, Wei

AU - Ruiz Velasco Hernandez, Andrea

AU - Wang, Shoubao

AU - Khan, Saba

AU - Zi, Min

AU - Jungmann, Andreas

AU - Camacho-Munoz, Maria Dolores

AU - Guo, Jing

AU - Du, Guanhua

AU - Xie, Liping

AU - Oceandy, Delvac

AU - Nicolaou, Anna

AU - Galli, Gina

AU - Müller, Oliver J.

AU - Cartwright, Elizabeth

AU - Ji, Yong

AU - Wang, Xin

PY - 2017/9/8

Y1 - 2017/9/8

N2 - 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. Cardiacspecificdeletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractilityandmitochondrial 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 integrityhas therapeutic potential for treating metabolic stress-induced cardiomyopathy.

AB - 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. Cardiacspecificdeletion of Erk5 in mice (Erk5-CKO) leads to dampened cardiac contractilityandmitochondrial 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 integrityhas therapeutic potential for treating metabolic stress-induced cardiomyopathy.

U2 - 10.1038/s41467-017-00664-8

DO - 10.1038/s41467-017-00664-8

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 494

ER -

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

Abstract

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