Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Nov;121(11):4281-8.
doi: 10.1172/JCI58554. Epub 2011 Oct 10.

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction

Simon Schenk  1 , Carrie E McCurdy, Andrew Philp, Mark Z Chen, Michael J Holliday, Gautum K Bandyopadhyay, Olivia Osborn, Keith Baar, Jerrold M Olefsky
Affiliations

Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction

Simon Schenk et al. J Clin Invest. 2011 Nov.

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 p55α/p50α 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Skeletal muscle Sirt1 deacetylase activity modulates enhanced in vivo insulin action after CR.
(A) Ac-p53 in skeletal muscle. p53 was immunoprecipitated from whole cell lysate (WCL) with anti-p53, and immunoprecipitates were immunoblotted with anti–acetyl lysine (Ac-Lys) and anti-p53. (B) Ac-Pgc1α in skeletal muscle. Acetylated proteins were immunoprecipitated from whole cell lysate with anti–acetyl lysine and immunoblotted for Pgc1α. Pgc1α was also measured in the whole cell lysate used for immunoprecipitation. (C) Blood glucose concentration and (D) area under the blood glucose curve (AUC) during an OGTT (1 g/kg). n = 8–10/group. (E) GINF, (F) IS-GDR, and (G) percentage suppression of HGP during a hyperinsulinemic-euglycemic clamp. n = 6–8/group. A 2-way ANOVA for main effects of diet and genotype was used for statistical analysis, with Tukey post-hoc test. *P < 0.05, within same genotype; #P < 0.05, within same diet group. Data are mean ± SEM.
Figure 2
Figure 2. CR enhances ex vivo insulin-stimulated skeletal muscle glucose uptake and Akt phosphorylation in a Sirt1 deacetylase-dependent manner.
(A) Insulin-stimulated (Insulin Stim.; 60 μU/ml) 2DOGU in isolated soleus and EDL muscles. Data are equal to insulin 2DOGU values minus basal 2DOGU values. DPM, disintegrations per minute. n = 6–8/group. (B) Percentage increase in 2DOGU above basal after insulin stimulation in isolated adipocytes. n = 5/group. (C) Representative blot of basal (B) and insulin-stimulated (I) phosphorylation of Akt (p-AktThr308, p-AktSer473, and total Akt ) in isolated soleus muscles. Phosphorylation values are corrected for total Akt and are normalized to their respective basal value. Values are presented relative to WT-AL. n = 5/group. (D) Phosphorylation of Ampk (p-AmpkThr172 corrected for Ampkα1/α2) in soleus muscle. n = 5/group. A 2-way ANOVA for main effects of diet and genotype was used for statistical analysis, with a Tukey post-hoc test. *P < 0.05, within same genotype; #P < 0.05, within same diet group. Data are presented as mean ± SEM.
Figure 3
Figure 3. CR reduces the expression of the p55α/p50α regulatory subunits of PI3K and enhances insulin-stimulated PI3K activation in skeletal muscle via Sirt1-mediated Stat3 deacetylation.
(A) Protein expression of the p85α/β, p55α, and p50α regulatory subunits of PI3K and Gapdh in soleus muscle. n = 5–6/group. (B) Basal and insulin-stimulated phosphotyrosine-associated (pY-associated) PI3K activity (n = 6–7/group) in soleus muscles. Note that in this image phosphoinositol 3-phopshate [PI(3)P] levels for insulin-stimulated KO AL muscle are less than those in the insulin-stimulated WT AL muscle. However, when the data are averaged across all samples and statistical analysis is performed, the data are as presented. (C) Acetylated Stat3 (n = 5/group), (D) Stat3 binding to a nonspecific region of the p85a gene upstream of the p50α start site (background) and the p55α and p50α promoters in the p85a gene, as measured by ChIP (n = 4/group), (E) input DNA for ChIP analysis, and (F) mRNA levels of p85a, p55a, and p50a (n = 6–7/group) in skeletal muscle. A 2-way ANOVA for main effects of diet and genotype was used for statistical analysis, with a Tukey post-hoc test. For PI3K activity, statistical analysis was conducted within the basal group only or within the insulin group only. *P < 0.05, within same genotype; #P < 0.05, within same diet group. Data are presented as mean ± SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lillioja S, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329(27):1988–1992. doi: 10.1056/NEJM199312303292703. - DOI - PubMed
    1. Cartee GD, Kietzke EW, Briggs-Tung C. Adaptation of muscle glucose transport with caloric restriction in adult, middle-aged, and old rats. Am J Physiol. 1994;266(5 pt 2):R1443–R1447. - PubMed
    1. McCurdy CE, Cartee GD. Akt2 is essential for the full effect of calorie restriction on insulin-stimulated glucose uptake in skeletal muscle. Diabetes. 2005;54(5):1349–1356. doi: 10.2337/diabetes.54.5.1349. - DOI - PubMed
    1. McCurdy CE, Davidson RT, Cartee GD. Brief calorie restriction increases Akt2 phosphorylation in insulin-stimulated rat skeletal muscle. Am J Physiol Endocrinol Metab. 2003;285(4):E693–E700. - PMC - PubMed
    1. McCurdy CE, Davidson RT, Cartee GD. Calorie restriction increases the ratio of phosphatidylinositol 3-kinase catalytic to regulatory subunits in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288(5):E996–E1001. doi: 10.1152/ajpendo.00566.2004. - DOI - PubMed

Publication types

MeSH terms