Contribution of Innate and Adaptive Exercise Capacity as Determinants of Health and Longevity in Rats

Abstract

Exercise capacity is a complex trait comprised of an inborn ability (i.e. innate component) in addition to that acquired in response to physical activity (i.e. adaptive component). In humans, it is near impossible to conduct an experiment that identifies which of these two components, innate or adaptive, is the leading mechanistic determinant underlying healthy aging and longevity. As a solution, we developed rat genetic models of both forms of exercise capacity via two‐way artificial selection: the innate (Low Capacity Runners LCR, High Capacity Runners HCR) and the adaptive (Low Response Trainers LRT, High Response Trainers HRT) to test our general thesis that low capacity for energy transfer underlies complex disease risk, accelerated aging, and diminished longevity. In previous work we showed that compared to HCR, LCR rats had 28–45 % shorter lifespan and that VO2max, maximal running capacity, and gains in body weight (↑% fat, ↓% lean) across lifespan predicted survivability.Conclusion 1: In rats, innate exercise capacity links with health and lifespanNow we aim to test the hypothesis that low adaptive capacity will have similar predictability features to the innate component. Here we studied 72 female and male LRT/HRT rats, representing the extremes of low and high adaptive capacity from generation 20 of selection, for treadmill exercise capacity across lifespan. As young adults (3 mo. old), female LRT and HRT in the non‐trained condition were similar for maximal running distance (605 ± 126 vs. 550 ± 137 meters, respectively) but due to bigger body mass, LRT > HRT for work performed (joules). Male LRT at 3 mo. old were significantly heavier, had higher running capacity and thus performed more work compared to HRT.Conclusion 2: When young, low adaptive capacity rats have greater body mass and perform more workAfter 8 weeks of endurance treadmill training, female HRT increased running distance by 437 ± 126 m and work performed by 269 ± 85 J. Whereas female LRT had no change in running capacity (−92 ± 100 m) or work performed (−2%). Male LRT and HRT demonstrated the same training response pattern for running capacity and work as females.Conclusion 3: As adults, high adaptive capacity rats improve both running capacity and work with training whereas low adaptive capacity rats do notAll rats were then left sedentary in home cages and re‐tested for exercise capacity at 22 mo. old. Using an NMR based analyzer, aged LRT females weighed 35 g more and had 5% less lean body mass and 35% greater body fat compared to aged HRT. Aged LRT males were 40 g heavier than HRT but with no significant differences in % lean or % fat body composition. With aging, all rats showed a significant decrease in running distance and capacity to perform work. However, aged female HRT ran 431 ± 143 m compared to 237 ± 55 m for aged female LRT, an equivalent to performing 58% more work. Aged male HRT ran 232 ± 73 m compared to 149 ± 59 m for aged male LRT, equating to 40% greater work performed by HRT compared to LRT.Conclusion 4: When aged, high adaptive capacity rats retain greater running capacity and can perform more work relative to their low adaptive capacity counterpartsTogether these data suggest that rats bred with low capacity for innate or low adaptive response to exercise are greater risk for premature aging and reduced survivability.Support or Funding InformationSupported by NIH grant P40OD021331 (LGK/SLB), Glenn Foundation for Medical Research N020308 (LGK). This work utilized Core Services supported by grant DK089503 of NIH to the University of Michigan.