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ResearchIn-Press PreviewCardiology Open Access | 10.1172/JCI162309

RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure

Tsunehisa Yamamoto,1 Santosh K. Maurya,2 Elizabeth Pruzinsky,1 Kirill Batmanov,1 Yang Xiao,3 Sarah M. Sulon,1 Tomoya Sakamoto,1 Yang Wang,2 Ling Lai,1 Kendra S. McDaid,1 Swapnil V. Shewale,1 Teresa C. Leone,1 Timothy R. Koves,4 Deborah M. Muoio,4 Pieterjan Dierickx,3 Mitchell A. Lazar,3 E. Douglas Lewandowski,2 and Daniel P. Kelly1

1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

Find articles by Yamamoto, T. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

Find articles by Sakamoto, T. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

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1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

Find articles by Lazar, M. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

Find articles by Lewandowski, E. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

2Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, United States of America

3Institute of Diabetes, Obesity, and Metabolism, and Division of Endocrinolo, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States of America

4Department of Medicine and Pharmacology, Duke University, Durham, United States of America

Find articles by Kelly, D. in: JCI | PubMed | Google Scholar |

Published March 16, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI162309.
Copyright © 2023, Yamamoto et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 16, 2023 - Version history
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Abstract

During development of heart failure, capacity for cardiomyocyte fatty acid oxidation (FAO) and ATP production is progressively diminished contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor interacting protein 140 (RIP140; Nrip1) has been shown to function as a transcriptional co-repressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibit increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and cardiomyocyte-specific RIP140 deficient (csNrip1-/-) mice were defended against development of heart failure caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in cardiomyocytes were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and FA utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for heart failure.

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