Differential Gene Expression in High- and Low-Active Inbred Mice

Abstract

Numerous candidate genes have been suggested in the recent literature with proposed roles in regulation of voluntary physical activity, with little evidence of these genes' functional roles. This study compared the haplotype structure and expression profile in skeletal muscle and brain of inherently high- (C57L/J) and low- (C3H/HeJ) active mice. Expression of nine candidate genes [Actn2, Actn3, Casq1, Drd2, Lepr, Mc4r, Mstn, Papss2, and Glut4 (a.k.a. Slc2a4)] was evaluated via RT-qPCR. SNPs were observed in regions of Actn2, Casq1, Drd2, Lepr, and Papss2; however, no SNPs were located in coding sequences or associated with any known regulatory sequences. In mice exposed to a running wheel, Casq1 (P = 0.0003) and Mstn (P = 0.002) transcript levels in the soleus were higher in the low-active mice. However, when these genes were evaluated in naïve animals, differential expression was not observed, demonstrating a training effect. Among naïve mice, no genes in either tissue exhibited differential expression between strains. Considering that no obvious SNP mechanisms were determined or differential expression was observed, our results indicate that genomic structural variation or gene expression data alone is not adequate to establish any of these genes' candidacy or causality in relation to regulation of physical activity.

Genetics of Regular Exercise and Sedentary Behaviors

“…Using their proteomics approach, Ferguson et al (2014), could not confirm a dopaminergic contribution to the heritability of voluntary wheel running in the same low-/highactive strain contrast and experimental setup used by Dawes et al (2014). They compared the global proteome signatures obtained from the nucleus accumbens of the C3H/HeJ and C57L/J inbred mice strains.…”

“…Dawes et al (2014) investigated cross-strain genomic variation and gene expression differences between low-active C3H/HeJ and high-active C57L/J inbred mice in nine of the genes with reported direct or indirect association to physical activity: actinin 2 (Actn2), actinin 3 (Actn3), calsequestrin 1 (Casq1), dopamine receptor 2 (Drd2), leptin receptor (Lepr), melacortin 4 receptor (Mcr4), myostatin (Mstn), 3 -phosphoadenosine 5 -phosphosulfate 2 (Papss2) and glucose transporter 4 (Glut4). First, between-strain structural genomic differences were identified in the haplotypes of Actn2, Casq1, Drd2, Lepr, and Papss2, but all SNPs differing between low-active and high active mice were non-coding, not in promoter regions, and not linked to known miRNA targets.…”

A novel mutation in Slc2a4 as a mouse model of fatigue

“…Mice from two N ‐ethyl‐ N ‐nitrosourea (ENU) lines show abnormal, low amplitude voluntary wheel‐running activity patterns. Circadian activity patterns are double plotted for ease of visualization, with each horizontal line representing 48 hours and successive days plotted along the Y‐axis. Wheel revolutions are depicted as black marks on the horizontal lines.…”

“…It seems logical that impaired glucose processing and homeostasis, with a concomitant altered tolerance of exercise, would cause aberrant patterns of voluntary wheel‐running activity. Voluntary wheel running is increased in mice overexpressing Glut4 in muscle, but GLUT4 expression does not differ between active and inactive mouse strains . It is likely, however, that impaired glucose transport and cellular utilization would have some effect on voluntary sustained activity.…”

“…Voluntary wheel running is increased in mice overexpressing Glut4 in muscle, 85 but GLUT4 expression does not differ between active and inactive mouse strains. 86 It is likely, however, that impaired glucose transport and cellular utilization would have some effect on voluntary sustained activity. Switching from predominantly glucose to fatty acid fuel utilization in muscle, either by transgenic or pharmacologic manipulation of the peroxisome proliferator-activated receptor delta (PPAR∂) pathway, increases exercise endurance in mice.…”