Can the inhibition of glycogen synthase kinase 3 mimic the physiological effects of exercise on muscle and other organs?

Regular exercise is widely recognized for its numerous health benefits, including enhancing overall well-being, reducing the risk of or alleviating symptoms from various chronic diseases, and slowing the aging process. Consequently, exercise extends the period of life free from long-term conditions and diseases, otherwise known as healthspan(definition). Even with this knowledge, the proportion of the global population that meets recommended physical activity levels remains startlingly low and has consistently decreased over time. Numerous individual and socioeconomic risk factors contribute to the sedentary lifestyle, which, along with the downward trend in physical activity, underscores the need to investigate the therapeutic potential of exercise mimetics. Glycogen synthase kinase 3 (GSK3) is a constitutively active enzyme that is inhibited by regular exercise in rodents. This review discusses recent work demonstrating how GSK3 inhibition, through pharmacological or genetic manipulation, can mimic the effects of exercise, along with possible pathways of action, particularly through the increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) – a central player in already established exercise mimetics. Our review focuses on two main outcomes commonly observed with exercise mimetics: improved endurance and the exertion of anti-obesity effects, including enhanced fat loss and insulin sensitivity. Additionally, since the existing exercise mimetics largely focus on replicating aerobic exercise by facilitating skeletal muscle adaptations, we center our review on this exercise modality and tissue. However, we also explore GSK3 inhibition and its potential to mimic resistance exercise, as well as its benefits to various tissues beyond skeletal muscle, including the heart, adipose tissue, bone, and brain. Finally, we propose future directions and experiments that could place GSK3 inhibition at the forefront of exercise mimetic research.