Diabetes (New York, N.Y.), 2013-10, Vol.62 (10), p.3404-3417
2013
Details
- Autor(en) / Beteiligte
- Titel
- Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation
- Ist Teil von
- Diabetes (New York, N.Y.), 2013-10, Vol.62 (10), p.3404-3417
- Ort / Verlag
- Alexandria, VA: American Diabetes Association
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0012-1797eISSN: 1939-327XDOI: 10.2337/db12-1650Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3781465
- Format
- –
- Schlagworte
- Acetylation, Acetyltransferases - metabolism, Animals, Biological and medical sciences, Blotting, Western, Diabetes. Impaired glucose tolerance, Endocrine pancreas. Apud cells (diseases), Endocrinopathies, Enzymes, Etiopathogenesis. Screening. Investigations. Target tissue resistance, Fasting, Fatty acids, Fundamental and applied biological sciences. Psychology, Gene Deletion, Gene Expression Regulation, Enzymologic, Glucose metabolism, Health aspects, Male, Mass spectrometry, Medical sciences, Metabolism, Metabolites, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria - enzymology, Mitochondria - metabolism, Muscle, Skeletal - enzymology, Muscle, Skeletal - metabolism, Muscles, Musculoskeletal system, Original Research, Oxidation-Reduction, Oxidative Stress, Phosphorylation, Sirtuin 3 - metabolism, Skeletal muscle, Striated muscle. Tendons, Vertebrates: osteoarticular system, musculoskeletal system