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Updated: May 28, 2026
Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
Published on: May 16, 2021
Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction
Simon Schenk1, Carrie E McCurdy, Andrew Philp
1Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673, USA.
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.
Insights
Caloric restriction improves skeletal muscle insulin sensitivity by activating sirtuin 1 (Sirt1). Sirt1 enhances insulin signaling and glucose uptake by modulating phosphoinositide 3-kinase (PI3K) pathways.
Area of Science:
- Metabolic signaling
- Molecular biology
- Endocrinology
Background:
- Skeletal muscle insulin resistance is central to type 2 diabetes development.
- Caloric restriction (CR) improves insulin sensitivity, but underlying molecular mechanisms are unclear.
- Sirtuin 1 (Sirt1) is implicated in energy metabolism and insulin action.
Purpose of the Study:
- To investigate the role of Sirt1 in mediating the effects of CR on skeletal muscle insulin sensitivity.
- To elucidate the molecular pathways linking CR, Sirt1, and improved insulin action.
Main Methods:
- Mice models with and without Sirt1 deacetylase activity were subjected to caloric restriction.
- Assessed insulin-stimulated phosphoinositide 3-kinase (PI3K) signaling and glucose uptake in skeletal muscle.
- Analyzed Sirt1-mediated deacetylation and inactivation of transcription factor Stat3.
Main Results:
- CR increased Sirt1 deacetylase activity in mouse skeletal muscle, enhancing insulin signaling and glucose uptake.
- Loss of Sirt1 deacetylase activity abolished CR-induced improvements in insulin action.
- Sirt1 deficiency prevented CR-induced inactivation of Stat3, leading to increased PI3K subunit expression.
Conclusions:
- Sirt1 is a critical signaling molecule linking caloric restriction to enhanced skeletal muscle insulin sensitivity.
- Sirt1 improves insulin action by deacetylating and inactivating Stat3, reducing PI3K subunit expression and optimizing PI3K signaling.