Creation of a Novel Inbred Mouse Model for High Activity with a Small Muscle Phenotype

Given challenges of studying skeletal form and function in humans, experimental models of skeletal loading are important for understanding both basic and applied questions of the musculoskeletal and associated physiological systems (e.g., energy balance, metabolism, behavior). Experimental approaches have frequently involved controlled loading, often axial loads placed on the ulna or tibia. Although appealing in allowing for precise estimates of stress and strain, these approaches often generate extremely high tissue strains, resulting in potentially pathological overload. Conversely, natural models of locomotor loading result in unknown levels of tissue strain but benefit by representing behaviors that animals will perform in life. Voluntary locomotion via an activity wheel can be used to explore the behavioral and physiological challenges of long‐term voluntary exercise. Furthermore, because activity is a heritable trait, it can be selected upon to gradually increase across generations. From an outbred experimental population of Hsd:ICR mice that had already experienced 51 generations of selective breeding for high levels of voluntary wheel‐running behavior (resulting in an approximately 2.5–3‐fold increase in activity over non‐selected controls), we began inbreeding via sib‐sib mating while simultaneously continuing selection for activity. These mice were also homozygous for an allele that results in an approximately 50% reduction in limb muscle mass. At generation 30 of inbreeding, the Hsd:ICR‐Myh4 minimsc mice were found to engage in an average of 487 minutes (females) and 371 minutes (males) of activity, with a mean speed of 13.1 m/min (females) and 14.7 m/min (males). These activity values place Hsd:ICR‐Myh4 minimsc at the high end of duration and the mid‐range of speed, when compared with other inbred strains. When housed without wheels and compared with outbred ICR mice, Hsd:ICR‐Myh4 minimsc mice have significantly lower body mass (27.9 ± 3.7 g sd vs 40.1 ± 5.9 g) and abdominal adipose tissue (0.18 ± 0.06 g vs. 0.30 ± 0.06 g) at 17 weeks of age. Compared with other inbred, high‐activity strains, Hsd:ICR‐Myh4 minimsc has advantages with good overall health, strong breeding success, and large litters (median 10 pups/litter). After 39 generations of brother‐sister mating, we estimate > 99.9% homozygosity, at which point the line was transferred to the Mutant Mouse Resource and Research Center, where it will be available to the community as a model system for studies of high voluntary exercise, energy balance, skeletal phenotypes, and musculoskeletal integration. Support or Funding Information NSF DEB‐1655362 (to TG); NIH NIAMS EARDA sub‐award from 5G11HD052368‐03 (to KMM); California University San Bernardino Department of Biology (to KMM); University of Missouri School of Medicine (to KMM) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .