Advanced Running Performance by Genetic Predisposition in Male Dummerstorf Marathon Mice (DUhTP) Reveals Higher Sterol Regulatory Element-Binding Protein (SREBP) Related mRNA Expression in the Liver and Higher Serum Levels of Progesterone

Ohde, Daniela; Moeller, Mark; Brenmoehl, Julia; Walz, Christina; Ponsuksili, Siriluck; Schwerin, Manfred; Fuellen, Georg; Hoeflich, Andreas

doi:10.1371/journal.pone.0146748

Cited by 6 publications

(5 citation statements)

References 56 publications

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

Control of Protein and Energy Metabolism in the Pituitary Gland in Response to Three-Week Running Training in Adult Male Mice

Walz

Brenmoehl

Trakooljul

et al. 2021

Cells

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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.

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Section: Discussionmentioning

confidence: 99%

Control of Protein and Energy Metabolism in the Pituitary Gland in Response to Three-Week Running Training in Adult Male Mice

Walz

Brenmoehl

Trakooljul

et al. 2021

Cells

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“…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 , 20 – 41 ]: Table S1) and selected at variable intensities (Additional file 2 : Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

Genomic characterization of the world’s longest selection experiment in mouse reveals the complexity of polygenic traits

et al. 2022

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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.

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“…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.…”

Section: Introductionmentioning

confidence: 80%

Metabolic Pathway Modeling in Muscle of Male Marathon Mice (DUhTP) and Controls (DUC)—A Possible Role of Lactate Dehydrogenase in Metabolic Flexibility

Brenmoehl

Brosig

Trakooljul

et al. 2023

Cells

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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.

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Advanced Running Performance by Genetic Predisposition in Male Dummerstorf Marathon Mice (DUhTP) Reveals Higher Sterol Regulatory Element-Binding Protein (SREBP) Related mRNA Expression in the Liver and Higher Serum Levels of Progesterone

Cited by 6 publications

References 56 publications

Control of Protein and Energy Metabolism in the Pituitary Gland in Response to Three-Week Running Training in Adult Male Mice

Control of Protein and Energy Metabolism in the Pituitary Gland in Response to Three-Week Running Training in Adult Male Mice

Genomic characterization of the world’s longest selection experiment in mouse reveals the complexity of polygenic traits

Metabolic Pathway Modeling in Muscle of Male Marathon Mice (DUhTP) and Controls (DUC)—A Possible Role of Lactate Dehydrogenase in Metabolic Flexibility

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