Molecular Underpinnings of Enduring Exercise Benefits

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Regular exercise exerts profound positive impacts on adult health, yet our understanding of the molecular mechanisms that establish and sustain systemic exercise benefits remains surprisingly incomplete. In particular, little is known of the molecules that maintain beneficial exercise outcomes after regular exercise is ended. We propose to address this knowledge gap from a new and tractable angle based on an exercise model in the simple animal C. elegans. Regular swim exercise in young adult C. elegans sets the animals on a trajectory of healthy aging that features better muscle, gut and neuronal functionality as compared to age-matched control animals that did not exercise in young adult life. Many of these healthy tissue outcomes endure for a remarkable proportion of adult life after the exercise period is over. Here we propose discovery-based work that will provide some of the first insights into the molecules required for lasting exercise effects, laying the foundation for deciphering the physiological mechanisms by which they exert these fascinating outcomes. Aim 1 is to decipher molecular mechanisms by which SOD-4 mediates maintained exercise benefits. Extracellular ecSOD promotes health resilience in humans and rodent models, and ecSOD expression is elevated by exercise. We found that C. elegans extracellular SOD-4 is required for long-lasting maintenance of exercise-induced locomotory improvements after exercise cessation, but is not required to establish these training outcomes. We will define roles of distinct membrane-spanning and secreted forms of SOD-4 in maintaining exercise benefits in muscle, gut and neuronal function, determine spatio-temporal SOD-4 distribution at the level of individual cells, address SOD-4 over-expression sufficiency for benefits, and test whether previously elaborated SOD-4 molecular signaling circuitry in C. elegans is analogously engaged to maintain exercise benefits. Aim 2 is to identify epigenetic factors required for enduring exercise benefits as a first step toward understanding molecular switches that might be triggered to affect long-lasting health-promoting physiology. We will test the hypothesis that exercise signals induce epigenetic modifications to confer systemic and lasting exercise benefits by disrupting genes encoding the 76 known modifiers of the C. elegans epigenome, including some previously implicated in redox biology, stress signaling and longevity. We expect our work to contribute a significant advance to the fields of exercise biology, aging, epigenetics, ROS signaling, and older-age health maintenance at the same time we establish the foundation for future mechanistic dissection. Given unequivocal evidence that exercise is the most effective pro-health, anti-disease intervention known in medicine, genetic dissection of exercise maintenance biology in native context, and over time, should yield new insights that guide strategies for improving human health and aging quality.