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

Walz, Christina; Brenmoehl, Julia; Trakooljul, Nares; Noce, Antonia; Caffier, Caroline; Ohde, Daniela; Langhammer, Martina; Wimmers, Klaus; Ponsuksili, Siriluck; Hoeflich, Andreas

doi:10.3390/cells10040736

Cited by 5 publications

(13 citation statements)

References 63 publications

(87 reference statements)

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“…The present study is based on an animal experiment described previously [ 9 ]. All experiments adhered to national and international standards, guidelines, and laws and were approved by the internal institutional committee and the state of Mecklenburg-Vorpommern (State Office for Agriculture, Food Safety, and Fisheries; AZ 7221.3-1-014/17, date of approval: 25 April 2017 and AZ 7221.3-1-064/19, date of approval: 30 January 2020).…”

Section: Methodsmentioning

confidence: 99%

“…Long-term selected mice of the Dummerstorf high treadmill line (DUhTP) were compared with their corresponding unselected control (DUC) without (sed) and with three weeks of treadmill training adapted to the performance capacity of the respective line (trained). According to the three-week training program, the mice were running five days per week (Monday to Friday) starting at the age of 49 days after birth [ 9 ]. All mice were sacrificed at day 70 of life, and different tissues were collected, including the pituitary gland and Musculus rectus femoris (Mrf).…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of total RNA derived from pituitary glands and Mrf, the generation of the DNA-Library, and the NGS procedure were performed and validated as previously described [9,Brenmoehl et al,submitted]. The obtained data were analyzed by comparing gene expression in the genetic groups (DUhTP and DUC) as well as the treatment groups (sedentary and trained).…”

Section: Next-generation Sequencing (Ngs) Differential Gene Expression Analysis and Data Processingmentioning

confidence: 99%

“…The following are available online at https://www.mdpi.com/article/ 10.3390/cells10123418/s1, Table S1: Effects of phenotype selection and endurance exercise on mRNA expression of other growth factors and receptors in the pituitary gland and muscle. Data Availability Statement: All data are available in the present manuscript, in the Supplement, in referenced manuscripts [9], or upon the request from the corresponding author.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…To do so, we compared a genetic model (DUhTP vs. DUC mice) and an experimental model (sedentary versus trained). We used two related RNAseq experiments, which studied mRNA expression in the pituitary gland [ 9 ] and muscle (Brenmoehl et al, submitted) by integrating the genetic model and training effects. Here, for the first time, we considered the interaction of two different tissues, the pituitary gland and muscle, with respect to phenotype selection and training.…”

Section: Introductionmentioning

confidence: 99%

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Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

Brenmoehl

Walz

Caffier

et al. 2021

Cells

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The somatotropic axis is required for a number of biological processes, including growth, metabolism, and aging. Due to its central effects on growth and metabolism and with respect to its positive effects on muscle mass, regulation of the GH/IGF-system during endurance exercise is of particular interest. In order to study the control of gene expression and adaptation related to physical performance, we used a non-inbred mouse model, phenotype-selected for high running performance (DUhTP). Gene expression of the GH/IGF-system and related signaling cascades were studied in the pituitary gland and muscle of sedentary males of marathon and unselected control mice. In addition, the effects of three weeks of endurance exercise were assessed in both genetic groups. In pituitary glands from DUhTP mice, reduced expression of Pou1f1 (p = 0.002) was accompanied by non-significant reductions of Gh mRNA (p = 0.066). In addition, mRNA expression of Ghsr and Sstr2 were significantly reduced in the pituitary glands from DUhTP mice (p ≤ 0.05). Central downregulation of Pou1f1 expression was accompanied by reduced serum concentrations of IGF1 and coordinated downregulation of multiple GH/IGF-signaling compounds in muscle (e.g., Ghr, Igf1, Igf1r, Igf2r, Irs1, Irs2, Akt3, Gskb, Pik3ca/b/a2, Pten, Rictor, Rptor, Tsc1, Mtor; p ≤ 0.05). In response to exercise, the expression of Igfbp3, Igfbp 4, and Igfbp 6 and Stc2 mRNA was increased in the muscle of DUhTP mice (p ≤ 0.05). Training-induced specific activation of AKT, S6K, and p38 MAPK was found in muscles from control mice but not in DUhTP mice (p ≤ 0.05), indicating a lack of mTORC1 and mTORC2 activation in marathon mice in response to physical exercise. While hormone-dependent mTORC1 and mTORC2 pathways in marathon mice were repressed, robust increases of Ragulator complex compounds (p ≤ 0.001) and elevated sirtuin 2 to 6 mRNA expression were observed in the DUhTP marathon mouse model (p ≤ 0.05). Activation of AMPK was not observed under the experimental conditions of the present study. Our results describe coordinated downregulation of the somatotropic pathway in long-term selected marathon mice (DUhTP), possibly via the pituitary gland and muscle interaction. Our results, for the first time, demonstrate that GH/IGF effects are repressed in a context of superior running performance in mice.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Next-generation Sequencing (Ngs) Differential Gene Expression Analysis and Data Processingmentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

Brenmoehl

Walz

Caffier

et al. 2021

Cells

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Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

Hammer,

Krzyzaniak,

Bahramnejad

et al. 2024

Clinical Science

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Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ~3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ~20 TCs (post-TC). In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.

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

Cited by 5 publications

References 63 publications

Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

Central Suppression of the GH/IGF Axis and Abrogation of Exercise-Related mTORC1/2 Activation in the Muscle of Phenotype-Selected Male Marathon Mice (DUhTP)

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy

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

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