2015
DOI: 10.2337/db14-1810
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SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat–Fed Mice

Abstract: Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, f… Show more

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Cited by 129 publications
(131 citation statements)
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“…These effects of NMN required cardiac expression of SIRT3 in the FXN-KO. Interestingly, SIRT3 was shown to be a crucial regulator of glucose flux in the skeletal muscle and heart under nutrient-overload conditions (60). SIRT3-KO mice stressed by a high-fat diet show a strong trending decrease (P = 0.065) in glucose uptake in the heart, as compared with high-fat-fed WT mice (60).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…These effects of NMN required cardiac expression of SIRT3 in the FXN-KO. Interestingly, SIRT3 was shown to be a crucial regulator of glucose flux in the skeletal muscle and heart under nutrient-overload conditions (60). SIRT3-KO mice stressed by a high-fat diet show a strong trending decrease (P = 0.065) in glucose uptake in the heart, as compared with high-fat-fed WT mice (60).…”
Section: Discussionmentioning
confidence: 99%
“…This reduction in glucose uptake was statistically significant in the skeletal muscle of SIRT3-KO mice. Loss of SIRT3 in the skeletal muscle impaired complex formation of mitochondrial proteins voltage-dependent anion channel (VDAC) and adenine nucleotide translocator (ANT), which resulted in decreased association of hexokinase II to the mitochondria, decreased conversion of glucose to G6P, and reduced downstream glucose metabolism (60,61). Given the SIRT3-dependent changes in glucose utilization and metabolism, and their potential role in the normalization of CE, it will be of interest to evaluate a regulatory role of SIRT3 on glucose metabolism within the FXN-KO heart.…”
Section: Discussionmentioning
confidence: 99%
“…The pathophysiological role of sirtuins deficiency in frailty could be related to the importance of these factors in skeletal muscle health (Tonkin et al, 2012). Sirtuins, in addition to increased proliferation of muscle progenitor cells (Rathbone et al, 2009), are key factors for preserving insulin sensitivity in skeletal muscle (Anderson et al, 2015;Lantier et al, 2015), an effect that seems to be related to their positive effect on mitochondrial function (Zhang et al, 2015b). Reduced skeletal muscle performance in response to exercise in aged mice is associated with lower activity of SIRT1 in this tissue, which is in turn related to an increase in poly (ADP-ribose) polymerase (PARP-1) activity that diminishes intracellular NAD levels.…”
Section: Sirtuinsmentioning
confidence: 99%
“…Despite the fact that mice lacking Sirt3 are phenotypically normal under basal conditions [57], Sirt3 deficient mice placed on a high fat diet (HFD) display accelerated development of metabolic syndrome including: accelerated insulin resistance, obesity, hyperlipidemia and steatohepatitis [58]. In mouse muscle, Sirt3 is necessary to preserve glucose oxidation and mitochondrial function thereby opposing the metabolic switch observed during HFD-induced insulin resistance [37,59,60]. In addition, Sirt3 has been directly linked to cardiomyocyte homeostasis by the observation that aged Sirt3-KO mice develop cardiac hypertrophy, a pathological condition caused by enlargement of the heart muscle that can lead to heart failure [41,61,62].…”
Section: Mitochondrial Sirtuins Protect Against Age-related Diseasesmentioning
confidence: 99%