PMID- 28887535
OWN - NLM
STAT- MEDLINE
DCOM- 20180115
LR  - 20220408
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Sep 8
TI  - Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction 
      due to attenuated Erk5 signaling.
PG  - 494
LID - 10.1038/s41467-017-00664-8 [doi]
LID - 494
AB  - 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 gamma 
      co-activator-1alpha (Pgc-1alpha) 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.The mechanistic link between metabolic stress and associated 
      cardiomyopathy is unknown. Here the authors show that high fat diet causes 
      calpain-1-dependent degradation of ERK5 leading to mitochondrial dysfunction, 
      suggesting the maintenance of cardiac ERK5 as a therapeutic approach for 
      cardiomyopathy prevention and/or treatment.
FAU - Liu, Wei
AU  - Liu W
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK. wei.liu@manchester.ac.uk.
FAU - Ruiz-Velasco, Andrea
AU  - Ruiz-Velasco A
AUID- ORCID: 0000-0003-0660-5855
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Wang, Shoubao
AU  - Wang S
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union 
      Medical College, Nanwei Road, Xuanwu District, Beijing, 100050, China.
FAU - Khan, Saba
AU  - Khan S
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Zi, Min
AU  - Zi M
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Jungmann, Andreas
AU  - Jungmann A
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120, Heidelberg, Germany.
FAU - Dolores Camacho-Munoz, Maria
AU  - Dolores Camacho-Munoz M
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Guo, Jing
AU  - Guo J
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Du, Guanhua
AU  - Du G
AD  - Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union 
      Medical College, Nanwei Road, Xuanwu District, Beijing, 100050, China.
FAU - Xie, Liping
AU  - Xie L
AD  - Key laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, 
      Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China.
FAU - Oceandy, Delvac
AU  - Oceandy D
AUID- ORCID: 0000-0002-6242-6491
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Nicolaou, Anna
AU  - Nicolaou A
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Galli, Gina
AU  - Galli G
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Muller, Oliver J
AU  - Muller OJ
AUID- ORCID: 0000-0001-8223-2638
AD  - Internal Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 
      69120, Heidelberg, Germany.
AD  - Department of Internal Medicine III, University of Kiel, Schittenhelmstrasse 12, 
      24105, Kiel, Germany.
FAU - Cartwright, Elizabeth J
AU  - Cartwright EJ
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK.
FAU - Ji, Yong
AU  - Ji Y
AD  - Key laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, 
      Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China. 
      yong.ji@njmu.edu.cn.
FAU - Wang, Xin
AU  - Wang X
AD  - Faculty of Biology, Medicine and Health, The University of Manchester, Michael 
      Smith Building, Oxford Road, Manchester, M13 9PT, UK. xin.wang@manchester.ac.uk.
LA  - eng
GR  - FS/15/16/31477/BHF_/British Heart Foundation/United Kingdom
GR  - PG/12/76/29852/BHF_/British Heart Foundation/United Kingdom
GR  - PG/14/70/31039/BHF_/British Heart Foundation/United Kingdom
GR  - PG/14/71/31063/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170908
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Fatty Acids)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 7)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.22.52 (Capn1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Calpain/genetics/metabolism
MH  - Cardiomyopathies/*etiology/metabolism/pathology
MH  - Cells, Cultured
MH  - Diet, High-Fat/adverse effects
MH  - Fatty Acids/pharmacology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Obese
MH  - Mitochondria, Heart/*metabolism
MH  - Mitogen-Activated Protein Kinase 7/genetics/*metabolism
MH  - Myocardium/metabolism/pathology
MH  - Myocytes, Cardiac/drug effects/metabolism/pathology
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/metabolism
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
PMC - PMC5591279
COIS- The authors declare no competing financial interests.
EDAT- 2017/09/10 06:00
MHDA- 2018/01/16 06:00
PMCR- 2017/09/08
CRDT- 2017/09/10 06:00
PHST- 2016/11/10 00:00 [received]
PHST- 2017/07/18 00:00 [accepted]
PHST- 2017/09/10 06:00 [entrez]
PHST- 2017/09/10 06:00 [pubmed]
PHST- 2018/01/16 06:00 [medline]
PHST- 2017/09/08 00:00 [pmc-release]
AID - 10.1038/s41467-017-00664-8 [pii]
AID - 664 [pii]
AID - 10.1038/s41467-017-00664-8 [doi]
PST - epublish
SO  - Nat Commun. 2017 Sep 8;8(1):494. doi: 10.1038/s41467-017-00664-8.