We used a novel mouse model to study the effects of selective breeding for high locomotor activity (14 generations) on relative organ sizes, hematocrit (Hct), and blood hemoglobin (Hb) concentration. We also examined effects of exercise training and genotype-by-environment interactions by housing animals for 8 weeks with wheels that were either free to rotate or locked. Mice from the four replicate High-Runner (HR) lines were smaller in total body mass but had larger body mass-adjusted kidneys relative to the four Control lines (P < 0.05). Control and HR lines did not differ significantly for mass-adjusted tail length or masses of the "triceps surae" hindlimb muscle group, heart (ventricle), spleen, liver, adrenal glands or gonads. Wheel access caused a reduction in body mass and an increase in relative heart mass. In females only, wheel access caused a reduction in relative spleen mass. Wheel access did not affect relative tail length or relative mass of the triceps surae, liver, adrenal gland or gonads. Significant interactions between selection history and wheel access were observed in females for spleen, liver, and gonad mass as well as Hct and Hb. Wheel access caused increases in both Hct and Hb, mainly in the HR lines. The mini-muscle phenotype, caused by a Mendelian recessive allele that halves hindlimb muscle mass, was significantly associated with several other body composition traits, including reduced body mass, increased tail length, increased heart mass, increased liver mass (females only), increased mean adrenal gland mass (females only), increased mean kidney mass (males only), and reduced Hct (wheel-access females only). Results are discussed in context of the beneficial acclimation hypothesis, genotype-by-environment interactions, and the potential for "nurture" to be self-reinforcing of "nature" in some complex behavioral-physiological phenotypes.