Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation
- Enxuan Jing1,
- Brian T. O’Neill1,
- Matthew J. Rardin2,
- André Kleinridders1,
- Olga R. Ilkeyeva3,
- Siegfried Ussar1,
- James R. Bain3,
- Kevin Y. Lee1,
- Eric M. Verdin4,5,
- Christopher B. Newgard3,
- Bradford W. Gibson2 and
- C. Ronald Kahn1⇑
- 1Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- 2Buck Institute for Research on Aging, Novato, California
- 3Department of Medicine, Duke University Medical Center, Durham, North Carolina
- 4Gladstone Institute of Virology and Immunology, San Francisco, California
- 5Department of Medicine, University of California, San Francisco, San Francisco, California.
- Corresponding author: C. Ronald Kahn, .
E.J. and B.T.O. contributed equally to this study.
Sirt3 is an NAD+-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion of Sirt3 led to impaired glucose oxidation in muscle, which was associated with decreased pyruvate dehydrogenase (PDH) activity, accumulation of pyruvate and lactate metabolites, and an inability of insulin to suppress fatty acid oxidation. Antibody-based acetyl-peptide enrichment and mass spectrometry of mitochondrial lysates from WT and Sirt3 KO skeletal muscle revealed that a major target of Sirt3 deacetylation is the E1α subunit of PDH (PDH E1α). Sirt3 knockout in vivo and Sirt3 knockdown in myoblasts in vitro induced hyperacetylation of the PDH E1α subunit, altering its phosphorylation leading to suppressed PDH enzymatic activity. The inhibition of PDH activity resulting from reduced levels of Sirt3 induces a switch of skeletal muscle substrate utilization from carbohydrate oxidation toward lactate production and fatty acid utilization even in the fed state, contributing to a loss of metabolic flexibility. Thus, Sirt3 plays an important role in skeletal muscle mitochondrial substrate choice and metabolic flexibility in part by regulating PDH function through deacetylation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1650/-/DC1.
- Received November 27, 2012.
- Accepted June 26, 2013.
- © 2013 by the American Diabetes Association.
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