Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure

Dao-Fu Dai; Yonggang Liu; Nathan Basisty; Pabalu Karunadharma; Somasish G Dastidar; Ying Ann Chiao; Tony Chen; Richard P Beyer; Michael T Chin; Michael Maccoss; Albert R La Spada; Peter S Rabinovitch

doi:10.1007/s11357-019-00119-6

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Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure

Journal article

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Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure

Dao-Fu Dai, Yonggang Liu, Nathan Basisty, Pabalu Karunadharma, Somasish G Dastidar, Ying Ann Chiao, Tony Chen, Richard P Beyer, Michael T Chin, Michael Maccoss, …

GeroScience, Vol.41(6), pp.847-860

12/2019

DOI: 10.1007/s11357-019-00119-6

PMCID: PMC6925086

PMID: 31650481

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Abstract

Inhibition of mammalian target of rapamycin complex I (mTORC1) by rapamycin improves cardiac function in both aging and heart failure. While the protective mechanisms are not fully understood in mammals, they are presumably mediated through metabolic regulation and suppression of protein translation by reduced phosphorylation of 4EBP1, a target of mTORC1. Using transverse aortic constriction (TAC) and Gαq overexpression-induced heart failure models, we examined the effect of cardiac-specific heterozygous deletion (het) of Raptor, a component of mTORC1, and cardiac-specific transgenic overexpression of wild type or phosphorylation site mutant 4EBP1. In wild-type mice with TAC-induced heart failure, quantitative shotgun proteomics revealed decreased abundance of proteins of mitochondrial metabolism and increased abundance of proteins in oxidative stress response, ubiquitin, and other pathways. The Raptor het ameliorated both TAC- and Gαq overexpression-induced heart failure and the associated proteomic remodeling, especially those pathways involved in mitochondrial function, citric acid cycle, and ubiquitination. In contrast, transgenic overexpression of either wild type or mutant 4EBP1 aggravated TAC and Gαq, consistent with reduced adaptive hypertrophy by suppression of protein translation, in parallel with adverse remodeling of left ventricular proteomes. Partial mTORC1 inhibition by Raptor heterozygous deletion ameliorates heart failure and is associated with better preservation of the mitochondrial proteome; however, this effect does not appear to be mediated through suppression of protein translation by increased 4EBP1. Increased activity of 4EBP1 reduced adaptive hypertrophy and aggravated heart failure, suggesting that protein translation is essential for adaptive hypertrophy in pressure overload.

Heart failure

Aging

mTOR

Nutrient signaling

Proteomics

Details

Title: Subtitle: Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure
Creators: Dao-Fu Dai - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. dao-fu-dai@uiowa.edu
Yonggang Liu - Department of Medicine, University of Washington, Seattle, WA, USA
Nathan Basisty - Department of Pathology, University of Washington, 1959 NE Pacific Ave, K081, Seattle, WA, 98195, USA
Pabalu Karunadharma - Department of Pathology, University of Washington, 1959 NE Pacific Ave, K081, Seattle, WA, 98195, USA
Somasish G Dastidar - Departments of Neurology, Duke University School of Medicine, Durham, NC, 27710, USA
Ying Ann Chiao - Department of Pathology, University of Washington, 1959 NE Pacific Ave, K081, Seattle, WA, 98195, USA
Tony Chen - Department of Pathology, University of Washington, 1959 NE Pacific Ave, K081, Seattle, WA, 98195, USA
Richard P Beyer - Department of Environmental Health and Biostatistics, University of Washington, Seattle, WA, USA
Michael T Chin - Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA
Michael Maccoss - Department of Genome Science, University of Washington, Seattle, WA, USA
Albert R La Spada - Duke Center for Neurodegeneration & Neurotherapeutics, Duke University School of Medicine, Durham, NC, 27710, USA
Peter S Rabinovitch - Department of Pathology, University of Washington, 1959 NE Pacific Ave, K081, Seattle, WA, 98195, USA. petersr@u.washington.edu
Resource Type: Journal article
Publication Details: GeroScience, Vol.41(6), pp.847-860
DOI: 10.1007/s11357-019-00119-6
PMID: 31650481
PMCID: PMC6925086
NLM abbreviation: Geroscience
ISSN: 2509-2715
eISSN: 2509-2723
Publisher: Switzerland
Grant note: R01 AG033082 / NIA NIH HHS P30AG013280 / NIA NIH HHS K08 HL145138 / NHLBI NIH HHS R01 HL101186 / NHLBI NIH HHS R01 AG038550 / NIA NIH HHS
Language: English
Date published: 12/2019
Academic Unit: Pathology; Iowa Neuroscience Institute; Radiation Oncology
Record Identifier: 9984070956002771

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