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Pathway analysis of microarray results related to Glycolysis and Gluconeogenesis (Mus musculus, WikiPathway WP157) in the liver of DUhTP versus DUC mice. Enzymatic reactions are marked by arrows. Blue arrows indicate specific glycolytic, red arrows specific gluconeogenic and black arrows enzymatic reactions for both glycolysis and gluconeogenesis. Enzyme encoding genes in boxes are colored red or blue, respectively, to indicate up- or down-regulation in DUhTP compared to control DUC. Different colors in a box for the same gene indicate various probe sets with differing expression. Two mRNA transcripts (GCK, GOT1) with fold change >2 are colored in pale and dark magenta for up- or down-regulation, respectively.
Source publication
Long-term-selected DUhTP mice represent a non-inbred model for inborn physical high-performance without previous training. Abundance of hepatic mRNA in 70-day male DUhTP and control mice was analyzed using the Affymetrix mouse array 430A 2.0. Differential expression analysis with PLIER corrected data was performed using AltAnalyze. Searching for ov...
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Citations
... The marathon mouse model DUhTP, generated by long-term paternal selection for high treadmill performance [23], is characterized by superior forced running performance but also by increased lipid accumulation. In response to voluntary moderate physical activity, increased lipid turnover has been observed in the liver [24,25] and adipose tissue [26], particularly subcutaneous fat [26,27], suggesting greater metabolic flexibility toward lipid metabolism in this mouse model. In this work, we used the marathon mice and a control strain, both derived from the same genetic background, to perform three weeks of treadmill training at an intensive speed that favors glycolytic utilization. ...
In contracting muscles, carbohydrates and fatty acids serve as energy substrates; the predominant utilization depends on the workload. Here, we investigated the contribution of non-mitochondrial and mitochondrial metabolic pathways in response to repeated training in a polygenic, paternally selected marathon mouse model (DUhTP), characterized by exceptional running performance and an unselected control (DUC), with both lines descended from the same genetic background. Both lines underwent three weeks of high-speed treadmill training or were sedentary. Both lines' muscles and plasma were analyzed. Muscle RNA was sequenced, and KEGG pathway analysis was performed. Analyses of muscle revealed no significant selection-related differences in muscle structure. However, in response to physical exercise, glucose and fatty acid oxidation were stimulated, lactate dehydrogenase activity was reduced, and lactate formation was inhibited in the marathon mice compared with trained control mice. The lack of lactate formation in response to exercise appears to be associated with increased lipid mobilization from peripheral adipose tissue in DUhTP mice, suggesting a specific benefit of lactate avoidance. Thus, results from the analysis of muscle metabolism in born marathon mice, shaped by 35 years (140 generations) of phenotype selection for superior running performance, suggest increased metabolic flexibility in male marathon mice toward lipid catabolism regulated by lactate dehydrogenase.
... double the litter size of the unselected mouse line) [7], body mass (approx. 90g body weight at 6 weeks of age) [8] and endurance (more than 3× higher untrained running capacity) [9,10]. Therefore, in order to elucidate the unpredictable polygenic background of these complex traits, where multiple genes, regulatory elements and pathways act in conjunction, the Dummerstorf trait-selected mouse lines represent a valuable resource. ...
... All these lines are still maintained, but selection only continues for DUK, DUC and DU6. Due to the long span of this selection experiment, lines have been given alternative names (Table 1, Additional file 3 [6,8,10,: Table S1) and selected at variable intensities (Additional file 2: Figure S2). ...
Background
Long-term selection experiments are a powerful tool to understand the genetic background of complex traits. The longest of such experiments has been conducted in the Research Institute for Farm Animal Biology (FBN), generating extreme mouse lines with increased fertility, body mass, protein mass and endurance. For >140 generations, these lines have been maintained alongside an unselected control line, representing a valuable resource for understanding the genetic basis of polygenic traits. However, their history and genomes have not been reported in a comprehensive manner yet. Therefore, the aim of this study is to provide a summary of the breeding history and phenotypic traits of these lines along with their genomic characteristics. We further attempt to decipher the effects of the observed line-specific patterns of genetic variation on each of the selected traits.
Results
Over the course of >140 generations, selection on the control line has given rise to two extremely fertile lines (>20 pups per litter each), two giant growth lines (one lean, one obese) and one long-distance running line. Whole genome sequencing analysis on 25 animals per line revealed line-specific patterns of genetic variation among lines, as well as high levels of homozygosity within lines. This high degree of distinctiveness results from the combined effects of long-term continuous selection, genetic drift, population bottleneck and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits.
Conclusions
The genomes of the Dummerstorf trait-selected mouse lines display distinct patterns of genomic variation harbouring multiple trait-relevant genes. Low levels of within-line genetic diversity indicate that many of the beneficial alleles have arrived to fixation alongside with neutral alleles. This study represents the first step in deciphering the influence of selection and neutral evolutionary forces on the genomes of these extreme mouse lines and depicts the genetic complexity underlying polygenic traits.
... Over the course of >140 generations, selection has shaped the genomes of the Dummerstorf traitselected mouse lines, leading to extreme phenotypes that include increased litter size (more than double the litter size of the unselected mouse line) 6 , body mass (approx. 90g body weight at 6 weeks of age) 7 and endurance (up to 3× higher untrained running capacity) 8 . ...
A unique set of mouse outbred lines has been generated through selective breeding in the longest selection experiment ever conducted on mice. Over the course of >140 generations, selection on the control line has given rise to two extremely fertile lines (>20 pups per litter each), two giant growth lines (one lean, one obese) and one long-distance running line. Genomic analysis revealed line-specific patterns of genetic variation among lines and high levels of homozygosity within lines as a result of long-term intensive selection, genetic drift and isolation. Detection of line-specific patterns of genetic differentiation and structural variation revealed multiple candidate genes behind the improvement of the selected traits. We conclude that the genomes of these lines are rich in beneficial alleles for the respective selected traits and represent an invaluable resource for unraveling the polygenic basis of fertility, obesity, muscle growth and endurance fitness.
... Integrin signaling was also identified, indicating differential effects on intracellular signaling pathways in trained DUhTP mice vs. unselected controls. Notably, in the liver of untrained DUhTP mice, activation of carbohydrate-, lipid-, and steroid metabolism was described compared to DUC mice [53]. ...
It is assumed that crosstalk of central and peripheral tissues plays a role in the adaptive response to physical activity and exercise. Here, we wanted to study the effects of training and genetic predisposition in a marathon mouse model on mRNA expression in the pituitary gland. Therefore, we used a mouse model developed by phenotype selection for superior running performance (DUhTP) and non-inbred control mice (DUC). Both mouse lines underwent treadmill training for three weeks or were kept in a sedentary condition. In all groups, total RNA was isolated from the pituitary gland and sequenced. Molecular pathway analysis was performed by ingenuity pathway analysis (IPA). Training induced differential expression of 637 genes (DEGs) in DUC but only 50 DEGs in DUhTP mice. Genetic selection for enhanced running performance strongly affected gene expression in the pituitary gland and identified 1732 DEGs in sedentary DUC versus DUhTP mice. Training appeared to have an even stronger effect on gene expression in both lines and comparatively revealed 3828 DEGs in the pituitary gland. From the list of DEGs in all experimental groups, candidate genes were extracted by comparison with published genomic regions with significant effects on training responses in mice. Bioinformatic modeling revealed induction and coordinated expression of the pathways for ribosome synthesis and oxidative phosphorylation in DUC mice. By contrast, DUhTP mice were resistant to the positive effects of three-week training on protein and energy metabolism in the pituitary gland.
... In addition, specific signatures were identified for lysine degradation and steroid biosynthesis. Interestingly, fatty acid biosynthesis and steroid biosynthesis were recently suggested also by the analysis of the hepatic transcriptome in DUhTP mice (Ohde et al. 2016). Moreover, higher plasma levels of progesterone were identified by LC-MS (Ohde et al. 2016), indicating that both the biosynthesis of fatty acids and steroids might also be controlled on the level of miRNA in DUhTP mice. ...
... Interestingly, fatty acid biosynthesis and steroid biosynthesis were recently suggested also by the analysis of the hepatic transcriptome in DUhTP mice (Ohde et al. 2016). Moreover, higher plasma levels of progesterone were identified by LC-MS (Ohde et al. 2016), indicating that both the biosynthesis of fatty acids and steroids might also be controlled on the level of miRNA in DUhTP mice. We may ask in a separate project, if lysine degradation has also to be considered in a context with fatty acid synthesis, because mitochondrial degradation of lysine via saccharopine results in the formation of acetyl-CoA (Goh et al. 2002), which can directly be used for fatty acid synthesis. ...
... Since AMPK plays a key role in the control of cellular energy homeostasis (Hardie et al. 2012), the miR-143-AKT-AMPK-axis may have physiological relevance in DUhTP mice. Of particular interest in our experimental system is the recent finding suggesting sterol-regulatory element-binding protein (SREBP) as an important transcriptional regulator of hepatic lipid synthesis in DUhTP mice (Ohde et al. 2016). ...
Dummerstorf marathon mice (DUhTP) are characterized by increased accretion of peripheral body fat with fast mobilization in response to mild physical activity if running wheels were included in their home cages. The obese phenotype coincides with elevated hepatic lipogenesis if compared to unselected controls. We now asked, if microRNA (miRNA) species present in the liver may contribute to the obese phenotype of DUhTP mice and if miRNAs respond to mild physical activity in our mouse model. Total RNA was extracted from livers of sedentary or physically active marathon mice and controls and analyzed by array hybridization or real-time PCR using locked nucleic acid probes. Pathway analysis of altered miRNA concentrations identified fatty acid biosynthesis as the most important target for the effects of miRNAs in the liver. A miRNA signature consisting of miR-21, 27, 33, 122, and 143 was present at higher abundance (p < 0.01) in the liver of sedentary or active DUhTP mice indicating involvement of miRNAs with hepatic lipogenesis. Furthermore, in protein lysates from the liver of DUhTP mice, significantly reduced concentrations of total and phosphorylated AKT and lower levels of phosphorylated AMPK were found (p < 0.05). Our results indicate active involvement of miRNAs in the control of hepatic energy metabolism and discuss effects on signal transduction as a potentially direct effect of miR-143 in the liver of DUhTP mice.
Marathon mice: researcher view on potential roles in preclinical research
