ArticleNature communications2017
Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 86 citations in OpenAlex.
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- Bone and Extracellular Signal-Related Kinase 5 (ERK5).Biomolecules · 2024Review
- ERK5 Interacts with Mitochondrial Glutaminase and Regulates Its Expression.International journal of molecular sciences · 2024Article
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- Promoting cardioprotection with fenugreek: Insights from CoClIranian journal of basic medical sciences · 2023Article
- The P21-Activated Kinase 1 and 2 As Potential Therapeutic Targets for the Management of Cardiovascular Disease.International journal of drug discovery and pharmacology · 2022Article
- Mitochondrial Cardiomyopathy: Molecular Epidemiology, Diagnosis, Models, and Therapeutic Management.Cells · 2022Review
- Effect of Extracellular Signal-Regulated Protein Kinase 5 Inhibition in Clear Cell Renal Cell Carcinoma.International journal of molecular sciences · 2022Article
- Mitochondrial Homeostasis in Obesity-related Hypertriglyceridemia.The Journal of clinical endocrinology and metabolism · 2022Article
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Authors and funding
17 authors at 4 institutions in 3 countries.
Funding
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.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.
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