Experimental evolution and phenotypic plasticity of hindlimb bones in high‐activity house mice

Abstract

Studies of rodents have shown that both forced and voluntary chronic exercise cause increased hindlimb bone diameter, mass, and strength. Among species of mammals, "cursoriality" is generally associated with longer limbs as well as relative lengthening of distal limb segments, resulting in an increased metatarsal/femur (MT/F) ratio. Indeed, we show that phylogenetic analyses of previously published data indicate a positive correlation between body mass-corrected home range area and both hindlimb length and MT/F in a sample of 19 species of Carnivora, although only the former is statistically significant in a multiple regression. Therefore, we used an experimental evolution approach to test for possible adaptive changes (in response to selective breeding and/or chronic exercise) in hindlimb bones of four replicate lines of house mice bred for high voluntary wheel running (S lines) for 21 generations and in four nonselected control (C) lines. We examined femur, tibiafibula, and longest metatarsal of males housed either with or without wheel access for 2 months beginning at 25-28 days of age. As expected from previous studies, mice from S lines ran more than C (primarily because the former ran faster) and were smaller in body size (both mass and length). Wheel access reduced body mass (but not length) of both S and C mice. Analysis of covariance (ANCOVA) revealed that body mass was a statistically significant predictor of all bone measures except MT/F ratio; therefore, all results reported are from ANCOVAs. Bone lengths were not significantly affected by either linetype (S vs. C) or wheel access. However, with body mass as a covariate, S mice had significantly thicker femora and tibiafibulae, and wheel access also significantly increased diameters. Mice from S lines also had heavier feet than C, and wheel access increased both foot and tibiafibula mass. Thus, the directions of evolutionary and phenotypic adaptation are generally consistent. Additionally, S-line individuals with the mini-muscle phenotype (homozygous for a Mendelian recessive allele that halves hindlimb muscle mass [Garland et al., 2002, Evolution 56:1,267-1,275]) exhibited significantly longer and thinner femora and tibiafibulae, with no difference in bone masses. Two results were considered surprising. First, no differences were found in the MT/F ratio (the classic indicator of cursoriality). Second, we did not find a significant interaction between linetype and wheel access for any trait, despite the higher running rate of S mice.

Functional Genomic Architecture of Predisposition to Voluntary Exercise in Mice: Expression QTL in the Brain

“…Wallingford et al (2009) observed that the inhibition of Prcp activity in vivo decreased food intake in wild-type and obese mice, and Prcp-null mice were leaner and shorter than wild-type controls and resistant to high-fat diet-induced obesity (Wallingford et al 2009). Similar phenotypes have been observed in the HR strain of mice utilized here (Swallow et al 1999;Kelly et al 2006;Vaanholt et al 2008).…”

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

“…In contrast, several findings in the Myh4 knockout strain do not closely match data from mini-muscle mice. For example, mini-muscle mice have longer tibiafibulae (Kelly et al 2006), eat more food per gram of body mass (Meek et al 2010), have disorganized muscle fibers in certain muscle regions (Guderley et al 2006(Guderley et al , 2008, and have reduced contractile speed (Syme et al 2005;McGillivray et al 2009), whereas none of those alterations have been reported in the Myh4 knockout mice. Some of the differences between the mice may be attributable to context (specific muscle studied, age, sex, rearing environment), while others may be due to the different types of mutations (null in the knockout and likely hypomorphic in the minimuscle mice.…”

“…It was hypothesized that the mini-muscle phenotype has functional characteristics that facilitate high levels of wheel running (Garland et al 2002), such as a doubled mass-specific aerobic capacity (Houle-Leroy et al 2003) and increased fatigue resistance in at least some hind-limb muscles (Syme et al 2005). Alternatively, the underlying allele might have pleiotropic effects that act on nonmuscle tissues and organs but still facilitate endurance running (e.g., reduced total body mass and fat mass; increased relative heart, liver, and kidney mass; longer hind-limb bones) (Garland et al 2002;Kelly et al 2006;Hannon et al 2008;Kolb et al 2010). However, at generation 22, wheel running of affected individuals did not differ statistically from those with normal-sized muscles (Garland et al 2002), and the magnitude of response to selection was not systematically higher in the two lines that had the mini-muscle phenotype as compared with the two that did not, indicating that multiple genetic "solutions" are possible in response to selection for high levels of voluntary exercise (Garland et al 2011a;Careau et al 2013).…”

Locomotor trade-offs in mice selectively bred for high voluntary wheel running

“…As a group, the four replicate selected lines show a diverse suite of morphological, biochemical, physiological, and behavioural differences from the four non-selected control lines (e.g. Swallow et al, 1999;Girard et al, 2001;Garland and Freeman, 2005;Kelly et al, 2006;Bilodeau et al, 2009;Rezende et al, 2009;Swallow et al, 2009).…”