title: 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.
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Royal Children's Hospital, Department of Paediatrics, Melbourne, Victoria, Australia; Fleur.garton@mcri.edu.au.
authors.forename: Fleur C
authors.identifier: http://orcid.org/0000-0002-1490-5930
authors.initials: FC
authors.lastname: Garton
authors.affiliation: Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Royal Children's Hospital, Department of Paediatrics, Melbourne, Victoria, Australia;
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan;
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Koch
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan;
authors.forename: Steven L
authors.initials: SL
authors.lastname: Britton
authors.affiliation: Department of Neurosciences, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol i Campus Can Ruti, Universitat Autònoma de Barcelona, Badalona, Spain; and.
authors.forename: Gisela
authors.initials: G
authors.lastname: Nogales-Gadea
authors.affiliation: Department of Neurosciences, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol i Campus Can Ruti, Universitat Autònoma de Barcelona, Badalona, Spain; and Instituto de Investigación Hospital 12 de Octubre (i+12) and Universidad Europea, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lucia
mesh_terms: D000185:Actinin / Q000172:deficiency; D000818:Animals; D004195:Disease Models, Animal; D015444:Exercise; D006009:Glycogen Storage Disease Type II / Q000503:physiopathology; D006012:Glycogen Storage Disease Type V / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D010805:Physical Conditioning, Animal; D051381:Rats
chemical_list: C118456:ACTN3 protein, human; D000185:Actinin
keywords: disease; exercise; genetic loci; humans; mice; performance; rats