Abstract
Chronic exercise is widely recognized as an important contributor to healthspan in humans and in diverse animal models. Recently, we have demonstrated that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits in flies and mice. Knockout of Sestrins prevents exercise adaptations to endurance and flight in Drosophila, and similarly prevents benefits to endurance and metabolism in exercising mice. In contrast, overexpression of dSestrin in muscle mimics several of the molecular and physiological adaptations characteristic of endurance exercise. Here, we extend those observations to examine the impact of dSestrin on preserving speed and increasing lysosomal activity. We find that dSestrin is a critical factor driving exercise adaptations to climbing speed, but is not absolutely required for exercise to increase lysosomal activity in Drosophila. The role of Sestrin in increasing speed during chronic exercise requires both the TORC2/AKT axis and the PGC1α homolog spargel, while dSestrin requires interactions with TORC1 to cell-autonomously increase lysosomal activity. These results highlight the conserved role of Sestrins as key factors that drive diverse physiological adaptations conferred by chronic exercise.
Highlights
As global populations age, the burden of caring for a disproportionately older demographic and their rising medical costs has become a major healthcare problem [1,2].Interventions that can preserve healthy function at advanced ages are of substantial importance
Muscle specific Drosophila Sestrin (dSesn) expression is sufficient to increase climbing speed in both a wild-type and dSesn-deficient background (Attp;Mef2 > dSesn cDNA14 of wild-type (dSesnWT), Sesn−/− ;Mef2 > dSesnWT ), whether exercised or not (Figure 1B). Both Sestrin and endurance exercise are known to enhance autophagy [13,29], so we examined autophagy-specific gene 8a (Atg8a) expression, a factor that controls the rate of autophagy [34], in these same flies
Atg8a expression whether exercised or not (Figure 1C). These results indicate that dSesn is required for exercise to induce increases in speed and Atg8a expression, and that overexpression of dSesn can mimic the effect of exercise on speed and Atg8a expression
Summary
The burden of caring for a disproportionately older demographic and their rising medical costs has become a major healthcare problem [1,2]. Interventions that can preserve healthy function at advanced ages are of substantial importance. Preservation of mobility is a major concern in aging populations, and declining mobility is associated with reduced independence [3]. Preservation of mobility allows individuals to continue social interactions, increasing personal satisfaction and morale into advanced age [4,5]. Identification of accessible, low-cost interventions that preserve healthy lifespan and mobility in the elderly would have widespread benefits, reducing healthcare costs and enhancing quality of life for aging individuals and those responsible for their care
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