Skip to main content

Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.

Publication ,  Journal Article
Jing, E; O'Neill, BT; Rardin, MJ; Kleinridders, A; Ilkeyeva, OR; Ussar, S; Bain, JR; Lee, KY; Verdin, EM; Newgard, CB; Gibson, BW; Kahn, CR
Published in: Diabetes
October 2013

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

October 2013

Volume

62

Issue

10

Start / End Page

3404 / 3417

Location

United States

Related Subject Headings

  • Sirtuin 3
  • Oxidative Stress
  • Oxidation-Reduction
  • Muscle, Skeletal
  • Mitochondria
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Gene Expression Regulation, Enzymologic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jing, E., O’Neill, B. T., Rardin, M. J., Kleinridders, A., Ilkeyeva, O. R., Ussar, S., … Kahn, C. R. (2013). Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes, 62(10), 3404–3417. https://doi.org/10.2337/db12-1650
Jing, Enxuan, Brian T. O’Neill, Matthew J. Rardin, André Kleinridders, Olga R. Ilkeyeva, Siegfried Ussar, James R. Bain, et al. “Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.Diabetes 62, no. 10 (October 2013): 3404–17. https://doi.org/10.2337/db12-1650.
Jing E, O’Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, et al. Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes. 2013 Oct;62(10):3404–17.
Jing, Enxuan, et al. “Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.Diabetes, vol. 62, no. 10, Oct. 2013, pp. 3404–17. Pubmed, doi:10.2337/db12-1650.
Jing E, O’Neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, Bain JR, Lee KY, Verdin EM, Newgard CB, Gibson BW, Kahn CR. Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes. 2013 Oct;62(10):3404–3417.

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

October 2013

Volume

62

Issue

10

Start / End Page

3404 / 3417

Location

United States

Related Subject Headings

  • Sirtuin 3
  • Oxidative Stress
  • Oxidation-Reduction
  • Muscle, Skeletal
  • Mitochondria
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Gene Expression Regulation, Enzymologic