Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation following endurance exercise

Andrew Philp, Ai Chen, Debin Lan, Gretchen A. Meyer, Anne N. Murphy, Amy E. Knapp, I. Mark Olfert, Carrie E. McCurdy, George R. Marcotte, Michael C. Hogan, Keith Baar, Simon Schenk

Research output: Contribution to journalArticle

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Abstract

The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-α coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise.

Original languageEnglish (US)
Pages (from-to)30561-30570
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number35
DOIs
StatePublished - Sep 2 2011

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Sirtuin 1
Peroxisome Proliferator-Activated Receptors
Organelle Biogenesis
Muscle
Durability
Skeletal Muscle
Acetyltransferases
Electron Transport
Running
Wheels
Association reactions
Acetylation
Exercise equipment
Proteins
Enzyme activity
Mitochondrial DNA
Immunoprecipitation
Immunoblotting
Carrier Proteins
Observation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation following endurance exercise. / Philp, Andrew; Chen, Ai; Lan, Debin; Meyer, Gretchen A.; Murphy, Anne N.; Knapp, Amy E.; Olfert, I. Mark; McCurdy, Carrie E.; Marcotte, George R.; Hogan, Michael C.; Baar, Keith; Schenk, Simon.

In: Journal of Biological Chemistry, Vol. 286, No. 35, 02.09.2011, p. 30561-30570.

Research output: Contribution to journalArticle

Philp, Andrew ; Chen, Ai ; Lan, Debin ; Meyer, Gretchen A. ; Murphy, Anne N. ; Knapp, Amy E. ; Olfert, I. Mark ; McCurdy, Carrie E. ; Marcotte, George R. ; Hogan, Michael C. ; Baar, Keith ; Schenk, Simon. / Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation following endurance exercise. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 35. pp. 30561-30570.
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abstract = "The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-α coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise.",
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AU - Philp, Andrew

AU - Chen, Ai

AU - Lan, Debin

AU - Meyer, Gretchen A.

AU - Murphy, Anne N.

AU - Knapp, Amy E.

AU - Olfert, I. Mark

AU - McCurdy, Carrie E.

AU - Marcotte, George R.

AU - Hogan, Michael C.

AU - Baar, Keith

AU - Schenk, Simon

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