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.