Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running

Abstract

SUMMARYTo examine the evolution of endurance-exercise behaviour, we have selectively bred four replicate lines of laboratory mice (Mus domesticus) for high voluntary wheel running (ʻhigh runnerʼ or HR lines), while also maintaining four non-selected control (C) lines. By generation 16, HR mice ran ~2.7-fold more than C mice, mainly by running faster (especially in females), a differential maintained through subsequent generations, suggesting an evolutionary limit of unknown origin. We hypothesized that HR mice would have higher glycogen levels before nightly running, show greater depletion of those depots during their more intense wheel running, and have increased glycogen synthase activity and GLUT-4 protein in skeletal muscle. We sampled females from generation 35 at three times (photophase 07:00 h-19:00 h) during days 5-6 of wheel access, as in the routine selection protocol: Group 1, day 5, 16:00 h-17:30 h, wheels blocked from 13:00 h; Group 2, day 6, 02:00 h-03:30 h (immediately after peak running); and Group 3, day 6, 07:00 h-08:30 h. An additional Group 4, sampled 16:00 h-17:30 h, never had wheels. HR individuals with the mini-muscle phenotype (50% reduced hindlimb muscle mass) were distinguished for statistical analyses comparing C, HR normal, and HR mini. HR mini ran more than HR normal, and at higher speeds, which might explain why they have been favored by the selective-breeding protocol. Plasma glucose was higher in Group 1 than in Group 4, indicating a training effect (phenotypic plasticity). Without wheels, no differences in gastrocnemius GLUT-4 were observed. After 5 days with wheels, all mice showed elevated GLUT-4, but HR normal and mini were 2.5-fold higher than C. At all times and irrespective of wheel access, HR mini showed approximately three-fold higher [glycogen] in gastrocnemius and altered glycogen synthase activity. HR mini also showed elevated glycogen in soleus when sampled during peak running. All mice showed some glycogen depletion during nightly wheel running, in muscles and/or liver, but the magnitude of this depletion was not large and hence does not seem to be limiting to the evolution of even-higher wheel running. Supplementary material available online at

Western diet increases wheel running in mice selectively bred for high voluntary wheel running

“…Starting in 1993, mice were bred for high voluntary wheel-running behavior (a major component of total voluntary locomotor activity when wheels are available), and after 16 generations, individuals from the four replicate high runner (HR) lines ran 2.5-3.0-fold as many revolutions per day as compared with those from four non-selected control (C) lines, a differential that has continued through more than 36 subsequent generations of selection. 8,9 Various changes in locomotor performance, behavior and neurobiology (especially related to motivation for wheel running) have been observed in the HR lines. [10][11][12] For instance, treadmill endurance capacity is elevated in HR mice, 13 as is maximal oxygen consumption.…”

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

“…In fact, recent work in human 'ultra-endurance' athletes (Pearson, 2006) suggests that neurobiological attributes make a greater contribution to maximum performance ability than has previously been acknowledged (Kayser, 2003;Baden et al, 2005;Noakes, 2007;Rose and Parfitt, 2007;Noakes, 2008). 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).…”

“…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). ]…”

Evolution of the additive genetic variance–covariance matrix under continuous directional selection on a complex behavioural phenotype

“…reduce or eliminate neophobia) and not part of the selection criterion, substantial correlated responses occurred for each of those days (figure 1a). On an absolute basis, HR mice show a greater daily increase than C mice in wheel running across the 6-day trial (figure 1c), which may require co-adaptational changes in training ability and other subordinate traits that support or cause wheel running [30]. The differential increase in wheel running is less apparent on a relative basis, especially after generation 24 (figure 1b).…”