Transcriptomic adaptations associated with enhanced skeletal muscle insulin sensitivity in response to dietary restriction and exercise training

Objective Dysregulation of skeletal muscle (SM) metabolism and insulin resistance are key defects of type 2 diabetes. Since dietary restriction and exercise are promising strategies to improve muscle insulin sensitivity, we aimed to uncover the underlying transcriptional signatures.

Methods We performed RNA-sequencing in SM of diabetes susceptible NZO mice in response to intermittent fasting (IF) or caloric restriction (CR) and in healthy C57BL/6J mice subjected to exercise.

Results CR and IF protected NZO mice from developing hyperglycemia, but only IF led to decreased body fat and higher insulin sensitivity compared to AL mice. This was accompanied by a significant upregulation of genes after IF, whereas CR predominantly decreased the expression of genes in SM. Although CR and IF share some of the top regulated genes, the overall gene profiles showed only minor similarities. Pathway analysis confirmed that IF and CR trigger distinct biological processes, including circadian rhythm and protein transport after IF and transcription and carbohydrate metabolism after CR. To identify genes whose expression is directly linked to an improved SM health, we compared the transcriptional changes after IF and CR in NZO to exercise in healthy mice. Interestingly, the gene set regulated by IF was more similar to exercise than to CR. Additionally, we identified 61 genes that were regulated by all three interventions, including genes that have not yet been described in the context of SM health.

Conclusion The beneficial effects of IF, CR and exercise on SM health are partly driven by common transcriptional responses.

Publication History

Article published online:
26 May 2022

• 1 Baumeier C, Schürmann A. (2015) Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. Biochim. Biophys. Acta - Mol. Cell Biol. Lipids. 1851; (5): 566-576 https://doi.org/10.1016/j.bbalip.2015.01.013
• 2 Kanzleiter T, Schürmann A. (2015) Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice. Am. J. Physiol. - Endocrinol. Metab 308(10): E912-E920 https://doi.org/10.1152/ajpendo.00289.2014