Original Full Length Article Effects of load-bearing exercise on skeletal structure and mechanics differ between outbred populations of mice Ian J. Wallace a, ⁎, Stefan Judex b , Brigitte Demes c a Department of Anthropology, Stony Brook University, Stony Brook, NY 11794, USA b Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794, USA c Department of Anatomical Sciences, Stony Brook University, Stony Brook, NY 11794, USA abstract article info Article history: Received 19 October 2014 Revised 15 November 2014 Accepted 17 November 2014 Available online 22 November 2014 Edited by David Fyhrie Keywords: Physical activity Mechanical loading Bone structure Bone mechanical properties Genetics Effects of load-bearing exercise on skeletal structure and mechanical properties can vary between inbred strains of mice. Here, we examine whether such variation also exists at the population level. An experiment was per- formed with two outbred mouse stocks that have been reproductively isolated for N 120 generations (Hsd:ICR, Crl:CD1). Growing females from each stock were either treated with a treadmill-running regimen for 1 month or served as controls. Limb forces were recorded with a force plate and cage activity monitored to verify that they were similar between stocks. After the experiment, femoral cortical and trabecular bone structure were quantified with micro-CT in the mid-diaphysis and distal metaphysis, respectively, and diaphyseal structural strength was determined with mechanical testing. Among Hsd:ICR mice, running led to significant improve- ments in diaphyseal bone quantity, structural geometry, and mechanical properties, as well as enhanced trabec- ular morphology. In contrast, among Crl:CD1 mice, the same running regimen had little effect on cortical and trabecular structure and significantly reduced diaphyseal resistance to fracture. In neither stock was body mass, muscle mass, or cage activity level different between runners and controls. Given that most environmental variables were controlled in this study, the differential effects of exercise on Hsd:ICR and Crl:CD1 bones were like- ly due to genetic differences between stocks. These results suggest that the benefits of loading for bone may vary between human populations (e.g., ethnic groups), in which case exercise programs and technologies designed to promote bone health with mechanical signals may be more advantageous to certain populations than others. © 2014 Elsevier Inc. All rights reserved. Introduction Studies of humans and animal models frequently demonstrate the potential for load-bearing exercise to augment skeletal structure and strength. In many cases, however, the skeletal benefits of exercise are found to vary between individuals, ranging from some individuals displaying substantial improvements to others remaining largely unaf- fected. Such studies underscore the fact that the responsiveness of an individual's bone to loading depends on a number of non-mechanical factors, particularly genetics [1–9], as well as age [10,11], sex [11–13], and others. Experiments with inbred mouse strains provide compelling evi- dence for the role of an individual's genome in modulating bone mechanoresponsiveness [1–9]. For example, exogenous limb loading studies have shown that certain inbred strains require more mechanical deformation in their bone diaphyses to trigger osteogenesis [4], and once the osteogenic threshold is surpassed, they exhibit less bone for- mation per unit increase of deformation [1,4,6]. The limb bones of par- ticular inbred strains are also less responsive to jumping and running exercise [2,9], as well as low-level mechanical vibration [3]. Mapping studies with inbred strain crosses have shown that numerous genomic regions harbor alleles that affect bone mechanotransduction [5,7,8], which heightens the potential for bone mechanoresponsiveness to vary from one individual to the next. Variation in skeletal adaptability to loading may also exist at the population level, that is, between groups of individuals that differ genet- ically and by demographic or environmental variables. For example, several ethnically distinct human populations are known to exhibit marked differences in skeletal structure and strength [14,15]; inasmuch as such differences are due to inter-group divergence in allele frequency [16], it is reasonable to hypothesize that one way in which gene poly- morphisms exert their influence on skeletal variation is by regulating bone mechanoresponsiveness [17,18]. The results of studies with inbred mice are of limited value in evaluating this hypothesis since each inbred strain is by definition genetically homogenous, unlike natural popula- tions that are genetically variable. Bone 72 (2015) 1–8 ⁎ Corresponding author. Fax: +1 631 632 9165. E-mail address: ian.wallace@stonybrook.edu (I.J. Wallace). http://dx.doi.org/10.1016/j.bone.2014.11.013 8756-3282/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone