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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\u2010running distance is used to explore the effects of selective breeding on the genetic \u201cbaseline\u201d 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\u2010line 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.<\/jats:p>","DOI":"10.1002\/ar.70133","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T11:53:52Z","timestamp":1769169232000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mice bred for increased running distance evolve\n                    <scp>3D<\/scp>\n                    shape differences in the hind limb skeleton but show limited plasticity in response to voluntary exercise"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-0268","authenticated-orcid":false,"given":"Amanda N.","family":"Smolinsky","sequence":"first","affiliation":[{"name":"Department of Anatomical Sciences Rocky Vista University  Englewood Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto A.","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Evolution, Ecology, and Organismal Biology University of California  Riverside California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7916-3552","authenticated-orcid":false,"suffix":"Jr.","given":"Theodore","family":"Garland","sequence":"additional","affiliation":[{"name":"Department of Evolution, Ecology, and Organismal Biology University of California  Riverside California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4704-1064","authenticated-orcid":false,"given":"Kevin M.","family":"Middleton","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences University of Missouri  Columbia Missouri USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Adams D. 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