The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner

Ping Li, Maria F. Newhardt, Satoshi Matsuzaki, Craig Eyster, Atul Pranay, Frederick F. Peelor, Albert Batushansky, Caroline Kinter, Kumar Subramani, Sandeep Subrahmanian, Jasimuddin Ahamed, Pengchun Yu, Michael Kinter, Benjamin F. Miller, Kenneth M. Humphries

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


SIRT3 is a longevity factor that acts as the primary deacetylase in mitochondria. Although ubiquitously expressed, previous global SIRT3 knockout studies have shown primarily a cardiac-specific phenotype. Here, we sought to determine how specifically knocking out SIRT3 in cardiomyocytes (SIRTcKO mice) temporally affects cardiac function and metabolism. Mice displayed an age-dependent increase in cardiac pathology, with 10-month-old mice exhibiting significant loss of systolic function, hypertrophy, and fibrosis. While mitochondrial function was maintained at 10 months, proteomics and metabolic phenotyping indicated SIRT3 hearts had increased reliance on glucose as an energy substrate. Additionally, there was a significant increase in branched-chain amino acids in SIRT3cKO hearts without concurrent increases in mTOR activity. Heavy water labeling experiments demonstrated that, by 3 months of age, there was an increase in protein synthesis that promoted hypertrophic growth with a potential loss of proteostasis in SIRT3cKO hearts. Cumulatively, these data show that the cardiomyocyte-specific loss of SIRT3 results in severe pathology with an accelerated aging phenotype.

Original languageEnglish
Pages (from-to)983-999
Number of pages17
Issue number2
StatePublished - 1 Apr 2023


  • Flexibility
  • Mitochondria
  • Proteostasis

ASJC Scopus subject areas

  • Aging
  • Veterinary (miscellaneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine


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