Rodent models for resolving extremes of exercise and health

Abstract

The extremes of exercise capacity and health are considered a complex interplay between genes and the environment. In general, the study of animal models has proven critical for deep mechanistic exploration that provides guidance for focused and hypothesis-driven discovery in humans. Hypotheses underlying molecular mechanisms of disease and gene/tissue function can be tested in rodents to generate sufficient evidence to resolve and progress our understanding of human biology. Here we provide examples of three alternative uses of rodent models that have been applied successfully to advance knowledge that bridges our understanding of the connection between exercise capacity and health status. First we review the strong association between exercise capacity and all-cause morbidity and mortality in humans through artificial selection on low and high exercise performance in the rat and the consequent generation of the "energy transfer hypothesis." Second we review specific transgenic and knockout mouse models that replicate the human disease condition and performance. This includes human glycogen storage diseases (McArdle and Pompe) and α-actinin-3 deficiency. Together these rodent models provide an overview of the advancements of molecular knowledge required for clinical translation. Continued study of these models in conjunction with human association studies will be critical to resolving the complex gene-environment interplay linking exercise capacity, health, and disease.

DNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging

“…The lines, termed the Low Capacity Runners (LCR) and the High Capacity Runners (HCR), differed by approximately 7-fold in running capacity after 27 generations of selective breeding. The sedentary HCR rats have increased mitochondrial content and function, are protected from the metabolic syndrome, hypertension, type 2 diabetes and cancer and have longer lifespan compared to the sedentary LCR rats (Garton et al, 2016). Since the HCR rats have metabolic phenotypes that resemble CR and DNA-PK-deficiency, we hypothesized that breeding for the HCR rats may have led to the generation of rats with decreased DNA-PK activity.…”

Acute and chronic changes in rat soleus muscle after high-fat high-sucrose diet

“…Using an animal model of high‐ and low‐capacity running, or equivalently, high‐ and low‐aerobic capacity (Garton et al. ; Thyfault and Wright ), previous studies demonstrated that both maintaining high oxidative capacity and improving oxidative capacity via exercise protects against structural and functional consequences due to high‐fat diet induced metabolic challenge. Mice that are selectively bred for high aerobic capacity demonstrate less intramuscular lipid in the medial gastrocnemius when given a high‐fat diet compared to low‐aerobic capacity animals (Noland et al.…”

Metabolic Scope as a Proximate Constraint on Individual Behavioral Variation: Effects on Personality, Plasticity, and Predictability

“…Indeed, recovery time from exhaustive exercise is faster for individual fish with larger scope (Marras et al 2009). Similarly, selectively bred lines of rats with greater aerobic scope respond more to exercise training than do unselected lines, suggesting that greater aerobic scope may provide a reserve capacity that can be exploited when elevated activity is needed (Novak et al 2009;Garton et al 2016). Further, a fast-growing chicken strain possessed greater aerobic scope than a slow-growing strain (Konarzewski et al .…”