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Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction.

ABSTRACT: Skeletal muscle insulin resistance is a key component of the etiology of type 2 diabetes. Caloric restriction (CR) enhances the sensitivity of skeletal muscle to insulin. However, the molecular signals within skeletal muscle linking CR to improved insulin action remain largely unknown. Recently, the mammalian ortholog of Sir2, sirtuin 1 (Sirt1), has been identified as a potential transducer of perturbations in cellular energy flux into subsequent metabolic adaptations, including modulation of skeletal muscle insulin action. Here, we have demonstrated that CR increases Sirt1 deacetylase activity in skeletal muscle in mice, in parallel with enhanced insulin-stimulated phosphoinositide 3-kinase (PI3K) signaling and glucose uptake. These adaptations in skeletal muscle insulin action were completely abrogated in mice lacking Sirt1 deacetylase activity. Mechanistically, Sirt1 was found to be required for the deacetylation and inactivation of the transcription factor Stat3 during CR, which resulted in decreased gene and protein expression of the p55?/p50? subunits of PI3K, thereby promoting more efficient PI3K signaling during insulin stimulation. Thus, these data demonstrate that Sirt1 is an integral signaling node in skeletal muscle linking CR to improved insulin action, primarily via modulation of PI3K signaling.

SUBMITTER: Schenk S

PROVIDER: S-EPMC3204844 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction.

Schenk Simon S McCurdy Carrie E CE Philp Andrew A Chen Mark Z MZ Holliday Michael J MJ Bandyopadhyay Gautum K GK Osborn Olivia O Baar Keith K Olefsky Jerrold M JM

The Journal of clinical investigation 20111010 11

Skeletal muscle insulin resistance is a key component of the etiology of type 2 diabetes. Caloric restriction (CR) enhances the sensitivity of skeletal muscle to insulin. However, the molecular signals within skeletal muscle linking CR to improved insulin action remain largely unknown. Recently, the mammalian ortholog of Sir2, sirtuin 1 (Sirt1), has been identified as a potential transducer of perturbations in cellular energy flux into subsequent metabolic adaptations, including modulation of sk ...[more]

PMID: 21985785

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Project description:ObjectiveDynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported a strong correlation between enhanced Drp1 activity and impaired skeletal muscle insulin sensitivity. This study aimed to determine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis.MethodsWe employed tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 knockout mice (mDrp1+/-). Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, followed by tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. In addition, we used primary human skeletal muscle cells (HSkMC) from lean, insulin-sensitive, and severely obese, insulin-resistant humans and transfected the cells with either a Drp1 shRNA (shDrp1) or scramble shRNA construct. Skeletal muscle and whole-body insulin sensitivity, skeletal muscle insulin signaling, mitochondrial network morphology, respiration, and H2O2 production were measured.ResultsPartial deletion of the Drp1 gene in skeletal muscle led to improved whole-body glucose tolerance and insulin sensitivity (P < 0.05) in diet-induced obese, insulin-resistant mice but not in lean mice. Analyses of mitochondrial structure and function revealed that the partial deletion of the Drp1 gene restored mitochondrial dynamics, improved mitochondrial morphology, and reduced mitochondrial Complex I- and II-derived H2O2 (P < 0.05) under the condition of diet-induced obesity. In addition, partial deletion of Drp1 in skeletal muscle resulted in elevated circulating FGF21 (P < 0.05) and in a trend towards increase of FGF21 expression in skeletal muscle tissue (P = 0.095). In primary myotubes derived from severely obese, insulin-resistant humans, ShRNA-induced-knockdown of Drp1 resulted in enhanced insulin signaling, insulin-stimulated glucose uptake and reduced cellular reactive oxygen species (ROS) content compared to the shScramble-treated myotubes from the same donors (P < 0.05).ConclusionThese data demonstrate that partial loss of skeletal muscle-specific Drp1 expression is sufficient to improve whole-body glucose homeostasis and insulin sensitivity under obese, insulin-resistant conditions, which may be, at least in part, due to reduced mitochondrial H2O2 production. In addition, our findings revealed divergent effects of Drp1 on whole-body metabolism under lean healthy or obese insulin-resistant conditions in mice.

Dataset Information

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction.

Publications

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction.

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