Journal article
Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation
Diabetes (New York, N.Y.), Vol.62(10), pp.3404-3417
10/2013
DOI: 10.2337/db12-1650
PMCID: PMC3781465
PMID: 23835326
Abstract
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.
Details
- Title: Subtitle
- Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation
- Creators
- Enxuan Jing - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MassachusettsBrian T O’Neill - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MassachusettsMatthew J Rardin - Buck Institute for Research on Aging, Novato, CaliforniaAndré Kleinridders - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MassachusettsOlga R Ilkeyeva - Department of Medicine, Duke University Medical Center, Durham, North CarolinaSiegfried Ussar - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MassachusettsJames R Bain - Department of Medicine, Duke University Medical Center, Durham, North CarolinaKevin Y Lee - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MassachusettsEric M Verdin - Gladstone Institute of Virology and Immunology, San Francisco, CaliforniaChristopher B Newgard - Department of Medicine, Duke University Medical Center, Durham, North CarolinaBradford W Gibson - Buck Institute for Research on Aging, Novato, CaliforniaC. Ronald Kahn - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.62(10), pp.3404-3417
- DOI
- 10.2337/db12-1650
- PMID
- 23835326
- PMCID
- PMC3781465
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- American Diabetes Association
- Language
- English
- Date published
- 10/2013
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984094644102771
Metrics
19 Record Views