Within-lifetime trade-offs but evolutionary freedom for hormonal and immunological traits: evidence from mice bred for high voluntary exercise

Abstract

SUMMARYChronic increases in circulating corticosterone (CORT) generally suppress immune function, but it is not known whether evolved increases necessarily have similar adverse effects. Moreover, the evolution of immune function might be constrained by the sharing of signaling molecules, such as CORT, across numerous physiological systems. Laboratory house mice (Mus domesticus Linnaeus) from four replicate lines selectively bred for high voluntary wheel running (HR lines) generally had baseline circulating CORT approximately twofold higher than in four non-selected control (C) lines. To test whether elevated baseline CORT suppresses the inflammatory response in HR mice, we injected females with lipopolysaccharide (LPS). All mice injected with LPS exhibited classic signs of an inflammatory response, including sickness behavior, loss of body mass, reduced locomotor activity (i.e. voluntary wheel running), enlarged spleens and livers, elevated hematocrit and elevated inflammatory cytokines. However, as compared with C mice, the inflammatory response was not suppressed in HR mice. Our results, and those of a previous study, suggest that selective breeding for high voluntary exercise has not altered immune function. They also suggest that the effects of evolved differences in baseline CORT levels may differ greatly from effects of environmental factors (often viewed as ʻstressorsʼ) that alter baseline CORT during an individualʼs lifetime. In particular, evolved increases in circulating levels of ʻstress hormonesʼ are not necessarily associated with detrimental suppression of the inflammatory response, presumably as a result of correlated evolution of other physiological systems (counter-measures). Our results have important implications for the interpretation of elevated stress hormones and of immune indicators in natural populations. Supplementary material available online at

Immune response to aTrichinella spiralisinfection in house mice from lines selectively bred for high voluntary wheel running

“…Malisch et al showed that, although HR and C mice did not differ statistically in the ability to clear an intestinal nematode infection (Nippostrongylus brasiliensis), an analysis of the eight line means revealed a negative relationship between clearance ability and baseline CORT levels, supporting the hypothesis that CORT has immunosuppressive effects (Malisch et al, 2009a). More recently, a study by Downs and colleagues also found no statistical difference between the HR and C lines following an immune challenge with lipopolysaccharide (Downs et al, 2012). Thus, evidence to date indicates that HR and C mice may be capable of similar immune responses to infection.…”

“…Assuming competing energetic demands and a limited energy supply or ability to process food, we predicted that parasitized animals would reduce voluntary activity levels to allow for an upregulation of immune function. A long-term experiment selectively breeding mice for high voluntary wheel running Rhodes et al, 2005;Garland et al, 2011a;Garland et al, 2011b) is particularly wellsuited to studies involving possible trade-offs between locomotion and other metabolically costly functions, including immune responses (Malisch et al, 2009a;Downs et al, 2012). Prior work shows that voluntary running can account for substantial fractions of daily energy expenditure (Rezende et al, 2009), and running in high voluntary wheel running (HR) lines has remained unchanged for >40 generations, despite continued selection, suggesting that it has reached an upper limit (Rezende et al, 2009;Kolb et al, 2010;Careau et al, 2013).…”

“…CORT is a steroid hormone well known to mobilize energy stores, particularly in times of increased stress. Malisch et al (Malisch et al, 2007) showed that CORT levels changed in response to selection in HR mice, whose CORT levels are approximately double those of C mice (see also Malisch et al, 2008;Malisch et al, 2009a;Downs et al, 2012). Running on wheels further elevates CORT levels Malisch et al, 2007), as CORT levels generally increase during exercise (Coleman et al, 1998).…”

“…As the spleen is considered to be an immunologically important organ (Corbin et al, 2008;Cowan et al, 2009;Schulte-Hostedde and Elsasser, 2011), spleen mass is expected to increase with infection. Additionally, hematocrit is expected to be positively correlated with both infection (Meagher, 1998;Downs et al, 2012) and V · O2max performance. Finally, we tested for effects of mini-muscle status Kelly et al, in press).…”

“…This phenotype is caused by a simple Mendelian recessive allele and is associated with alterations in various morphological, physiological and behavioral traits, including organ size, response to a lipopolysaccharide (LPS) immune challenge, and wheel running under some conditions (e.g. Garland et al, 2002;Houle-Leroy et al, 2003;Swallow et al, 2005;Syme et al, 2005;Rezende et al, 2006;Dlugosz et al, 2009;Downs et al, 2012).…”