The Effects of Muscle-Specific GSK3 Reduction on Murine Muscle Contractility and Metabolism in Female Mice

Abstract

Background: Glycogen synthase kinase 3 (GSK3) is a constitutively active serine/threonine protein kinase. Originally identified in skeletal muscle for its role in glucose homeostasis, GSK3 also negatively regulates muscle size and the transcription of genes associated with the oxidative phenotype. Previous studies have found that GSK3 inhibition improves whole-body metabolism and muscle quality in male mice. However, many physiological dissimilarities between male and female mice have been observed, specifically in terms of metabolic regulation; and it is currently unknown as to whether the effects of GSK3 inhibition observed in male mice are reproducible in female mice. Therefore, this study examined the effects of a muscle-specific GSK3 reduction on whole-body metabolism and muscle force production in female mice. We hypothesized that the muscle-specific reduction of GSK3 would improve glucose tolerance and muscle force production in female mice. Methods: A skeletal-muscle specific GSK3 partial (~50%) knockdown model (GSK3mKD) was generated on a C57BL/6J background. Experiments were conducted on female mice aged 2-4 months, with flox littermates (GSK3floxed) serving as controls (n = 6 per group). During the 7-week intervention, dual-energy X-ray absorptiometry (DXA) scans were completed at baseline and week 7. On weeks 5 and 7, mice were housed in a Promethion metabolic cage system for 48hours. Glucose and insulin tolerance tests (GTT, ITT) were completed on week 6. At time of euthanasia, soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected and subjected to isolated skeletal muscle force frequency contractile experiments. Results: There was a main effect of body mass demonstrating that GSK3mKD mice were heavier than GSK3flox mice due to an increase in fat mass ( p = 0.02) and a trending increase in lean mass ( p = 0.08). There were no differences in cage activity, food intake, daily energy expenditure (DEE), respiratory exchange ratio, glucose- or insulin tolerance. There was a significant increase in force production in the EDL ( p = 0.005), which we attribute to a trending increase in cross-sectional area ( p = 0.08). In contrast, there were no differences in force production in the SOL. Conclusion: This study found that the muscle-specific partial knockdown of GSK3 increased body mass, but did not alter the metabolic phenotype (i.e., DEE or whole-body glucose regulation) in female mice, which is in contrast with GSK3 inhibition studies previously conducted in male mice. Furthermore, force production only increased in the EDL, which was primarily due to an increase in muscle size. In conclusion, there appears to be differences in the response to GSK3 inhibition in male and female mice, and future studies in our lab will examine the potential cellular mechanisms. CIHR Canada Research Chairs Program This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.