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

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.

• Authors: 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
• Journal: GeroScience (Geroscience) Vol. 41 Issue 6 Pg. 847-860 (12 2019) ISSN: 2509-2723 [Electronic] Switzerland
• PMID: 31650481 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Proteome
• DNA
• Mechanistic Target of Rapamycin Complex 1
• Sirolimus

Topics

• Animals
• Blotting, Western
• DNA (genetics)
• Disease Models, Animal
• Gene Expression Regulation
• Heart Failure (drug therapy, genetics, metabolism, physiopathology)
• Immunosuppressive Agents (pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors, genetics)
• Mice
• Mice, Transgenic
• Proteome
• Signal Transduction
• Sirolimus (pharmacology)