Combined overexpression of SIRT1 and knockout of GCN5 in adult skeletal muscle does not affect glucose homeostasis or exercise performance in mice

Abstract

Sirtuin 1 (SIRT1) and general control of amino acid synthesis 5 (GCN5) regulate mitochondrial biogenesis via opposing modulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) acetylation status and activity. However, the combined contribution of SIRT1 and GCN5 to skeletal muscle metabolism and endurance performance in vivo is unknown. In this study, we investigated the impact of combined skeletal muscle-specific overexpression of SIRT1 and deletion of GCN5 on glucose homeostasis, skeletal muscle mitochondrial biogenesis and function, and metabolic adaptation to endurance exercise training in mice. We generated mice with combined and tamoxifen-inducible skeletal muscle-specific overexpression of SIRT1 and knockout of GCN5 (dTG) and floxed [wild type (WT)] littermates using a Cre-LoxP approach. All mice were treated with tamoxifen at 5–6 wk of age, and 4–7 wk later glucose homeostasis, skeletal muscle contractile function, mitochondrial function, and the effects of 14 days of voluntary wheel running on expression of metabolic proteins and exercise capacity were assessed. There was no difference in oral glucose tolerance, skeletal muscle contractile function, mitochondrial abundance, or maximal respiratory capacity between dTG and WT mice. Additionally, there were no genotype differences in exercise performance and markers of mitochondrial biogenesis after 14 days of voluntary wheel running. These results demonstrate that combined overexpression of SIRT1 and loss of GCN5 in vivo does not promote metabolic remodeling in skeletal muscle of sedentary or exercise-trained mice.

Role of Histone Deacetylases in Skeletal Muscle Physiology and Systemic Energy Homeostasis: Implications for Metabolic Diseases and Therapy

“…Researchers further generated skeletal muscle-specific SIRT1-mKO mice and found that mKO mice lost the effect of CR-induced increasing insulin sensitivity and were unable to deacetylate and inactivate STAT3, resulting in upregulating the phosphatidylinositol-3-kinase (PI3K) inhibitory regulator p55α/p50α expression (Schenk et al, 2011). Although knockout or overexpression of SIRT1 in skeletal muscles has no effect on endurance capacity or glucose homeostasis in mice (Gurd et al, 2009;Philp et al, 2011;White et al, 2013;Svensson et al, 2020), some studies have shown that AMPK regulates energy metabolism of skeletal muscles partially mediated by SIRT1, and SIRT1 is significantly increased after endurance exercise (Suwa et al, 2008;Canto et al, 2009). Overexpression of Sirt1 in skeletal muscles by adeno-associated virus 1 (AAV1) promotes the expression of oxidation-related genes including Ppargc1a, Tfam, Cpt1b, and Pdk4, while it has no effect on insulin sensitivity of body (Vila et al, 2016).…”

Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review

“…Exercise as well as diets can activate the AMPK/SIRT1/PGC1α axis [ 583 , 584 , 585 , 592 , 597 , 598 , 599 ]. Resveratrol and telmisartan activate the SIRT1/PGC1α and AMPK/SIRT1 pathways, to increase mitochondrial activity and aerobic capacity in muscle cells, respectively [ 589 , 590 ]. In addition, hyperinsulinemia increases SIRT1 expression in muscle tissue [ 610 ].…”

“…However, in mice, upregulation of SIRT1 alone is not correlated to an enhanced glucose homeostasis or to mitochondrial biogenesis as compared to wild type during exercise training [ 590 ]. This observation indicates that, even though SIRT1 is upregulated during exercise in skeletal muscle, increased levels do not mediate an enhanced response.…”

“…This observation indicates that, even though SIRT1 is upregulated during exercise in skeletal muscle, increased levels do not mediate an enhanced response. Thus, other factors during exercise may be more important to regulate physiological response [ 590 ]. In mice, resveratrol increases mitochondrial activity and aerobic capacity in muscle cells through activation of the SIRT1/PGC1α pathway [ 591 ].…”

GCN5 Maintains Muscle Integrity by Acetylating YY1 to Promote Dystrophin Expression

“…From these findings arose the hypothesis that GCN5 deletion could drive PGC-1αdirected mitochondrial biogenesis in muscle. However, recent work could not identify a metabolic role for GCN5 in skeletal muscle (Dent et al, 2017;Svensson et al, 2020).…”