title: Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.
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.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Enxuan
authors.initials: E
authors.lastname: Jing
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Rardin
authors.forename: André
authors.initials: A
authors.lastname: Kleinridders
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkeyeva
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ussar
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.forename: Eric M
authors.initials: EM
authors.lastname: Verdin
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Bradford W
authors.initials: BW
authors.lastname: Gibson
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005215:Fasting; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D056566:Sirtuin 3 / Q000378:metabolism*
chemical_list: C525046:Sirt3 protein, mouse; D000123:Acetyltransferases; D056566:Sirtuin 3