Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Open accessAbstract
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.
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Sirtuins control metabolic flux through the TCA cycle, insulin sensitivity, and PGC-1α activity.
“Members of this family control metabolic flux through the tricarboxylic acid (TCA) cycle, insulin sensitivity [38], and PGC-1α activity [39].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [38]
SIRT1 is activated by caloric restriction.
“SIRT1 is activated by caloric restriction [38]”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [38]
Deacetylase activity of SIRT1 in skeletal muscle is increased in animals on a 20-day caloric restriction diet (60% of ad libitum intake), concomitant with enhanced insulin signaling and glucose uptake.
“Notably, deacetylase activity of SIRT1 in skeletal muscle is increased in animals on a 20-day caloric restriction diet (60% of ad libitum intake), concomitant with enhanced insulin signaling and glucose uptake [72].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [72]
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- Authors
- Schenk, S., McCurdy, C. E., Philp, A., Chen, M. Z., Holliday, M. J., Bandyopadhyay, G. K., Osborn, O., Baar, K., & Olefsky, J. M.
- Affiliations
- University of California San Diego (US)
- University of Colorado Anschutz (US)
- University of California, Davis (US)
- Corresponding author
- Olefsky, Jerrold M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-11-01
- Volume
- 121
- Issue
- 11
- Pages
- 4281-4288
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3204844
- OpenAlex
- W2115982791
- Cited by
- 197
- References
- 54
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 14 · 2020: 11 · 2019: 17 · 2018: 14 · 2017: 13 · 2016: 14 · 2015: 18 · 2014: 18 · 2013: 22 · 2012: 24
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- American Diabetes Association (UL1 RR024146)
- National Institutes of Health (DK-033651, HD 057022, HD012303, DK 074868, DK-063491, RR024146)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK 074868, DK 033651, T32DK007494, R37DK033651, P01DK074868, R01DK033651, P30DK063491)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR058878)
- National Center for Research Resources (UL1RR024146)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD057022, U54HD012303, R24HD050837)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- SIRT1, caloric restriction, skeletal muscle insulin sensitivity, insulin resistance, type 2 diabetes, PI3K signaling, glucose uptake, Sir2, energy metabolism
- MeSH terms
- Animals, Base Sequence, Diabetes Mellitus, Type 2, Insulin Resistance, Male, Mice, Inbred C57BL, Glucose Clamp Technique, Signal Transduction, DNA Primers, Mice, Knockout, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Caloric Restriction, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice, Sirtuin 1
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