Mice bred for increased running distance evolve 3D shape differences in the hind limb skeleton but show limited...

Skeletal morphology is determined by a combination of genetic background and phenotypic plasticity induced by mechanical loading across the lifespan (e.g., exercise), among other factors. Changes in limb morphology associated with locomotor activity experienced throughout individual ontogeny and in species over evolutionary time can provide insight into the adaptation of vertebrate locomotor systems. Here, a mouse line artificially selected for increased voluntary wheel-running distance is used to explore the effects of selective breeding on the genetic "baseline" morphology of the hind limb skeleton and to describe its plastic response to chronic exercise, including potential genotype by environment interactions. This experimental design additionally allowed for testing two hypotheses: (1) that bone plasticity itself is a trait that can evolve in direction and magnitude, and (2) that bone plasticity can influence the trajectory of selection for locomotor phenotypes. Using a combination of 3D shape analyses, we find that 82 generations of selective breeding result in substantial changes in the morphology of the hind limb skeleton, as well as subtle changes in the skeletal response to exercise that support the evolvability of bone plasticity (i.e., skeletal plasticity differs based on genetic background). We additionally find that the evolved bone shape of selected mice does not resemble the plastic exercise response of control-line animals. These results provide further evidence of genetic variations among populations in the plastic bone response to mechanical loading and inform our understanding of the plastic and evolutionary lability of the skeletal system in response to locomotor demands.