SIRT1 Deacetylase Activity Is Not Required For Contraction-Induced Mitochondrial Biogenesis In Skeletal Muscle

Abstract

The class III NAD+-dependent protein deacetylase, sirtuin1 (SIRT1), has been proposed as a key integrator/regulator of mitochondrial biogenesis in skeletal muscle due to its sensitivity to NAD+ and its ability to increase the activity of the transcriptional co-activator, PGC-1α. PURPOSE: To determine whether muscle-specific deletion of SIRT1 deacetylase activity (mKOSIRT1) blunts mitochondrial biogenesis following acute (AEX) or chronic (CEX) endurance exercise. METHODS: To generate mKOSIRT1, mice in which exon 4 of the SIRT1 gene was floxed, were crossed with MCK-Cre mice, resulting in offspring with muscle-specific "knockout" of deacetylase activity. For CEX studies, mKOSIRT1 and wildtype/floxed (WT) mice had free access to a running wheel for 21 days, after which skeletal muscle electron transport chain (ETC) enzyme activity and markers of mitochondrial biogenesis were measured. For AEX studies, mice ran for 1h on a motorized treadmill and skeletal muscle gene expression and PGC-1α acetylation status were measured 3h post-exercise. RESULTS: In WT mice, CEX increased mitochondrial and PGC-1α protein abundance, ETC enzyme activity and mtDNA content (P<0.05), and, importantly, this enhancement was not impaired in mKOSIRT1 mice. After AEX, PGC-1α expression was increased in both groups (∼4 fold; P<0.05), and increased to a greater extent in the mKOSIRT1 compared to WT mice (P<0.05). In addition, AEX increased the expression of a number of PGC-1α target genes including PPARα, CPT1, cytochrome-c and mitofusin-2, with the induction similar (2-4 fold) between mKOSIRT1 and WT mice (P<0.05). Interestingly, we also found that PGC-1α was deacetylated to the same extent in mKOSIRT1 and WT mice (P<0.05), suggesting that SIRT1 is not the primary regulator of PGC-1α acetylation status, in vivo. CONCLUSION: Altogether, our data suggest that, 1) SIRT1 activity is not required for endurance training-induced mitochondrial biogenesis in skeletal muscle and, 2) a protein other than SIRT1 mediates PGC-1α deacetylation after exercise.