Erythropoietin elevates but not voluntary wheel running in mice

Abstract

SUMMARYVoluntary activity is a complex trait, comprising both behavioral (motivation, reward) and anatomical/physiological (ability) elements. In the present study, oxygen transport was investigated as a possible limitation to further increases in running by four replicate lines of mice that have been selectively bred for high voluntary wheel running and have reached an apparent selection limit. To increase oxygen transport capacity, erythrocyte density was elevated by the administration of an erythropoietin (EPO) analogue. Mice were given two EPO injections, two days apart, at one of two dose levels (100 or 300gkg -1 and 300gkg -1 dose levels (overall mean of 4.5gdl -1 increase). EPO treatment significantly increased V O2,max by ~5% in both the HR and C lines, with no dose ϫ line type interaction. However, wheel running (revolutions per day) did not increase with EPO treatment in either the HR or C lines, and in fact significantly decreased at the higher dose in both line types. These results suggest that neither [Hb] per se nor V O2,max is limiting voluntary wheel running in the HR lines. Moreover, we hypothesize that the decrease in wheel running at the higher dose of EPO may reflect direct action on the reward pathway of the brain.Key words: artificial selection, central limitation, experimental evolution, maximum metabolic rate, oxygen transport, peripheral limitation, respiratory exchange ratio, selection limit, symmorphosis. THE JOURNAL OF EXPERIMENTAL BIOLOGY 511Erythropoietin elevates V O 2 ,max in mice aerobically supported exercise has also increased in the HR lines, as demonstrated by increased endurance (Meek et al., 2009) and increases maximum oxygen consumption [V O2,max (Swallow et al., 1998b;Rezende et al., 2005;Rezende et al., 2006a)] during forced treadmill exercise. However, the trait, or group of traits, that is limiting to even higher levels of wheel running in the HR lines remains an open question. Results to date indicate that glycogen depletion during nightly running is not responsible for the limitation (Gomes et al., 2009) nor are the HR mice limited by their ability to process enough energy to support the increased energy demands of running (Koteja et al., 1999;Koteja et al., 2001;Vaanholt et al., 2007a;Rezende et al., 2009).One of the main predictors of endurance-running ability is wholeorganism aerobic capacity (Wagner, 1996;Bassett and Howley, 2000;Lucia et al., 2001;Calbet et al., 2006;Noakes, 2007;Levine, 2008;Noakes, 2009). All else being equal, the higher the maximum aerobic capacity, the higher the maximum sustainable running speed. Maximum oxygen consumption defines the upper limits of the cardiovascular/respiratory system and of aerobic ability in general (for a review, see Levine, 2008). The ultimate determinant of organismal aerobic capacity occurs at the 'sink' of tissue oxygen consumption but all of the sequential steps of oxygen transport, from ventilatory convection in the lungs to oxygen diffusion in the peripheral tissues, contribute to V O2,max (Taylor an...

Mice selectively bred for high voluntary wheel running have larger midbrains: support for the mosaic model of brain evolution

“…As compared with C mice, HR mice exhibit various anatomical (Garland and Freeman, 2005;Kelly et al, 2006) and physiological differences (Rezende et al, 2006a;Rezende et al, 2006b;Gomes et al, 2009;Meek et al, 2009) that appear to support their 2.5-to 3-fold greater daily wheelrunning distances. Although previous studies have revealed physiological (Dumke et al, 2001;Rezende et al, 2006a;Rezende et al, 2006b;Gomes et al, 2009;Meek et al, 2009;Kolb et al, 2010), morphological (Garland and Freeman, 2005;Kelly et al, 2006) and motivational (Rhodes et al, 2005; Belke and Garland, 2007) components underlying this HR phenotype, the present findings are the first evidence of neuroanatomical changes in the HR lines. [A previous study that quantified volume of the dentate gyrus of the hippocampus found no statistical difference between the HR and C lines (Rhodes et al, 2003a). ]…”

“…In our laboratory, selection for high voluntary wheel running in outbred laboratory house mice has been ongoing for more than 60 generations, and has resulted in numerous physiological (Girard et al, 2007;Malisch et al, 2008;Gomes et al, 2009;Meek et al, 2009), behavioral (Rhodes et al, 2001Rhodes and Garland, 2003; Belke and Garland, 2007;Meek et al, 2010), and neurobiological (Rhodes et al, 2003a;Rhodes et al, 2003b) changes in four replicate high-runner (HR) lines of mice as compared with four non-selected control (C) lines. Moreover, a recent comparative study demonstrated a positive correlation between brain size and an index of exercise capacity, maximal oxygen consumption (Raichlen and Gordon, 2011), one of the traits that has increased in the HR lines (Rezende et al, 2006b;Kolb et al, 2010). Therefore, in this study we tested whether selective breeding for high voluntary wheel running in house mice has altered their brain size.…”

“…Mini-muscle individuals also differ from wild-type individuals in the size of some internal organs, including the heart, liver, spleen, lungs and kidneys [adjusting for variation in body size (e.g. Garland et al, 2002;Meek et al, 2009;Kolb et al, 2010; Downs et al, 2012)]. Therefore, it seemed reasonable to expect that minimuscle individuals might also differ in relative brain size.…”

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

“…After 10 generations of selection, mice from the four replicate High Runner (HR) lines were running .70% more revolutions per day (on days 5 and 6) as compared with four nonselected control (C) lines (Swallow et al 1998). Wheel running continued to increase in the HR lines until generation 16-28 (depending on line and sex) and remained approximately at those levels through a subsequent 50 generations of selective breeding Swallow et al 2009;Kolb et al 2010;Careau et al 2012Careau et al , 2013.…”

“…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).…”