Activation of proteostasis pathways after acute exercise in C. elegans

Abstract

Exercise is one of the most potent interventions known that is able to prevent and even treat dozens of age-related dysfunctions and diseases. Despite this, much remains unknown about how its benefits are derived. Because exercise exerts such wide-ranging effects, and because a decline in protein homeostasis (proteostasis) with age has been connected to numerous age-related diseases, I hypothesized that exercise could increase the activity of proteostasis pathways like the proteasome and autophagy and that this could ameliorate age-related declines in function. I decided to use a Caenorhabditis elegans exercise paradigm to explore the effects exercise has on proteostasis because of its inherent advantages that make it an appealing model organism. Recent studies of involuntary thrashing (swimming) in C. elegans found that it was able to replicate numerous aspects of mammalian exercise, including increased mitochondrial function, increased muscle function, and gene expression profiles that resemble mammalian endurance exercise. I used this thrashing exercise paradigm to look at effects of acute exercise and the effects of multiple days of exercise on aging and proteostasis, including the autophagy-lysosome system, the proteasome, and toxic peptides. I found that exercise is able to increase proteasomal activity and autophagic flux in vivo, improved resistance to toxic peptides, and increased lifespan. One of the primary rationales for studying the mechanisms of exercise is to uncover potential mediators that can be repurposed to deliver the benefits of exercise to those unable to engage in physical activity. I hypothesized that exercise-elevated metabolite alpha-ketoglutarate, already demonstrated to improve age-related declines in flies and mice, would mimic the effects of exercise on proteostasis. Interestingly, treatment with alpha-ketoglutarate showed mixed results on measures of proteostasis, indicative of the challenges in recapitulating a complex phenomenon like exercise.