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Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: evidence for altered mitochondrial function and amino acid metabolism.

ABSTRACT: Numerous genetic manipulations that extend lifespan in mice have been discovered over the past two decades, the most robust of which has arguably been the down regulation of growth hormone (GH) signaling. However, while decreased GH signaling has been associated with improved health and lifespan, many of the underlying physiological changes and molecular mechanisms associated with GH signaling have yet to be elucidated. To this end, we have completed the first transcriptomic and metabolomic study on long-lived growth hormone releasing hormone knockout (GHRH-KO) and wild-type mice in brown adipose tissue (transcriptomics) and blood serum (metabolomics). We find that GHRH-KO mice have increased transcript levels of mitochondrial and amino acid genes with decreased levels of extracellular matrix genes. Concurrently, mitochondrial metabolites are differentially regulated in GHRH-KO. Furthermore, we find a strong signal of genotype-by-sex interactions, suggesting the sexes have differing physiological responses to GH deficiency. Overall, our results point towards a strong influence of mitochondrial metabolism in GHRH-KO mice which potentially is tightly intertwined with their extended lifespan phenotype.

SUBMITTER: Hoffman JM

PROVIDER: S-EPMC7066919 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

Project description:Numerous genetic manipulations that extend lifespan in mice have been discovered over the past two decades, the most robust of which has arguably been the down regulation of growth hormone (GH) signaling. However, while decreased GH signaling has been associated with improved health and lifespan, many of the underlying physiological changes and molecular mechanisms have yet to be elucidated. To this end, we have completed the first transcriptomic and metabolomic study on long-lived growth hormone releasing hormone knockout (GHRH-KO) and wild-type mice in brown adipose tissue (transcriptomics) and blood serum (metabolomics). We find that GHRH-KO mice have increased transcript levels of mitochondrial and amino acid genes with decreased levels of extracellular matrix genes. Concurrently, mitochondrial metabolites are differentially regulated in GHRH-KO. Furthermore, we find a strong signal of genotype-by-sex interactions, suggesting the sexes have differing physiological responses to GH deficiency. Overall, our results point towards a strong influence of mitochondrial metabolism in GHRH-KO mice which potentially is tightly intertwined with their extended lifespan phenotype.

2020-03-30 | GSE143672 | GEO

Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

Project description:Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: Evidence for altered mitochondrial function and amino acid metabolism

| PRJNA601215 | ENA

Insulin sensitivity in long-lived growth hormone-releasing hormone knockout mice.

Project description:Our previous studies showed that loss-of-function mutation of growth hormone releasing hormone (GHRH) results in increased longevity and enhanced insulin sensitivity in mice. However, the details of improved insulin action and tissue-specific insulin signaling are largely unknown in this healthy-aging mouse model. We conducted hyperinsulinemic-euglycemic clamp to investigate mechanisms underlying enhanced insulin sensitivity in growth hormone (GH) deficient mice. Further, we assessed in vivo tissue-specific insulin activity via activation of PI3K-AKT and MAPK-ERK1/2 cascades using western blot. Clamp results showed that the glucose infusion rate required for maintaining euglycemia was much higher in GHRH-/- mice compared to WT controls. Insulin-mediated glucose production was largely suppressed, whereas glucose uptake in skeletal muscle and brown adipose tissue were significant enhanced in GHRH-/- mice compared to WT controls. Enhanced capacity of insulin-induced activation of the PI3K-AKT and MAPK-ERK1/2 signaling were observed in a tissue-specific manner in GHRH-/- mice. Enhanced systemic insulin sensitivity in long-lived GHRH-/- mice is associated with differential activation of insulin signaling cascades among various organs. Improved action of insulin in the insulin sensitive tissues is likely to mediate the prolonged longevity and healthy-aging effects of GH deficiency in mice.

| S-EPMC7585079 | biostudies-literature

Bex1 knock out mice show altered skeletal muscle regeneration.

Project description:Bex1 and Calmodulin (CaM) are upregulated during skeletal muscle regeneration. We confirm this finding and demonstrate the novel finding that they interact in a calcium-dependent manner. To study the role of Bex1 and its interaction with CaM in skeletal muscle regeneration, we generated Bex1 knock out (Bex1-KO) mice. These mice appeared to develop normally and are fertile, but displayed a functional deficit in exercise performance compared to wild type (WT) mice. After intramuscular injection of cardiotoxin, which causes extensive and reproducible myotrauma followed by recovery, regenerating muscles of Bex1-KO mice exhibited elevated and prolonged cell proliferation, as well as delayed cell differentiation, compared to WT mice. Thus, our results provide the first evidence that Bex1-KO mice show altered muscle regeneration, and allow us to propose that the interaction of Bex1 with Ca(2+)/CaM may be involved in skeletal muscle regeneration.

| S-EPMC2265538 | biostudies-literature

Targeted Metabolomic Profiling Reveals Association Between Altered Amino Acids and Poor Functional Recovery After Stroke.

Project description:Amino acids have been shown to be among the most important metabolites to be altered following stroke; however, they are a double-edged sword with regard to regulating hemostasis. In this study, we conducted a targeted metabolomic study to examine the association between serum levels of amino acids and functional recovery after stroke. Three hundred and fifty-one patients with stroke admitted to an acute rehabilitation hospital were screened, and 106 patients were selected based on inclusion and exclusion criteria. Recruited patients were stratified using Montebello Rehabilitation Factor Score (MRFS) efficiency. We selected the top (n = 20, 19%) and bottom (n = 20, 19%) of MRFS efficiency for metabolomic analysis. A total of 21 serum amino acids levels were measured using ultra high performance liquid chromatography and mass spectrometry. The normalized data were analyzed by multivariate approaches, and the selected potential biomarkers were combined in different combinations for prediction of stroke functional recovery. The results demonstrated that there were significant differences in leucine-isoleucine, proline, threonine, glutamic acid, and arginine levels between good and poor recovery groups. In the training (0.952) and test (0.835) sets, metabolite biomarker panels composed of proline, glutamic acid, and arginine had the highest sensitivity and specificity in distinguishing good recovery from poor. In particular, arginine was present in the top 10 combinations of the average area under the receiver operating characteristic curve (AUC) test set. Our findings suggest that amino acids related to energy metabolism and excitotoxicity may play an important role in functional recovery after stroke. Therefore, the level of serum arginine has predictive value for the recovery rate after stroke.

| S-EPMC7001531 | biostudies-literature

Altered Phenotypes of Breast Epithelial × Breast Cancer Hybrids after ZEB1 Knock-Out.

Project description:ZEB1 plays a pivotal role in epithelial-to-mesenchymal transition (EMT), (cancer) cell stemness and cancer therapy resistance. The M13HS tumor hybrids, which were derived from spontaneous fusion events between the M13SV1-EGFP-Neo breast epithelial cells and HS578T-Hyg breast cancer cells, express ZEB1 and exhibit prospective cancer stem cell properties. To explore a possible correlation between the ZEB1 and stemness/ EMT-related properties in M13HS tumor hybrids, ZEB1 was knocked-out by CRISPR/Cas9. Colony formation, mammosphere formation, cell migration, invasion assays, flow cytometry and Western blot analyses were performed for the characterization of ZEB1 knock-out cells. The ZEB1 knock-out in M13HS tumor cells was not correlated with the down-regulation of the EMT-related markers N-CADHERIN (CDH2) and VIMENTIN and up-regulation of miR-200c-3p. Nonetheless, both the colony formation and mammosphere formation capacities of the M13HS ZEB1 knock-out cells were markedly reduced. Interestingly, the M13HS-2 ZEB1-KO cells harbored a markedly higher fraction of ALDH1-positive cells. The Transwell/ Boyden chamber migration assay data indicated a reduced migratory activity of the M13HS ZEB1-knock-out tumor hybrids, whereas in scratch/ wound-healing assays only the M13SH-8 ZEB1-knock-out cells possessed a reduced locomotory activity. Similarly, only the M13HS-8 ZEB1-knock-out tumor hybrids showed a reduced invasion capacity. Although the ZEB1 knock-out resulted in only moderate phenotypic changes, our data support the role of ZEB1 in EMT and stemness.

| S-EPMC10744253 | biostudies-literature

Metabolomic Characterization of Knock-Out Mutants in Arabidopsis - Development of a Metabolite Profiling Database for Knock-Out Mutants in Arabidopsis (MeKO)

Project description:Despite recent intensive research efforts in functional genomics, the functions of only a limited number of Arabidopsis (Arabidopsis thaliana) genes have been determined experimentally. Thus, improving gene annotation remains a major challenge in plant science. Because metabolite profiling can characterize the metabolomic phenotype of a genetic perturbation of plant metabolism, it provides clues to the function of genes of interest. In this regard, we chose 50 Arabidopsis mutants including a set of characterized and uncharacterized mutants, which resemble wild-type plants. We performed metabolite profiling of the plants using gas chromatography-mass spectrometry (GC-MS). To make the dataset available as an efficient public functional genomics tool for hypothesis generation, we developed the MeKO database, which allows evaluation of whether a mutation affects metabolism during normal growth. This database contains images of mutants, statistical data analyses, and data on differential metabolite accumulation. Non-processed data, including chromatograms, mass spectra, and experimental meta-data, follow the guidelines of the Metabolomics Standards Initiative (MSI) and are freely downloadable. Proof-of-concept analysis suggests that the MeKO database is highly useful for gene annotation and for generation of hypotheses for genes of interest. MeKO is publicly available at http://prime.psc.riken.jp/meko/.

2014-03-01 | MTBLS47 | MetaboLights

Ca2+-signaling in airway smooth muscle cells is altered in T-bet knock-out mice.

Project description:BackgroundAirway smooth muscle cells (ASMC) play a key role in bronchial hyperresponsiveness (BHR). A major component of the signaling cascade leading to ASMC contraction is calcium. So far, agonist-induced Ca2+-signaling in asthma has been studied by comparing innate properties of inbred rat or mouse strains, or by using selected mediators known to be involved in asthma. T-bet knock-out (KO) mice show key features of allergic asthma such as a shift towards TH2-lymphocytes and display a broad spectrum of asthma-like histological and functional characteristics. In this study, we aimed at investigating whether Ca2+-homeostasis of ASMC is altered in T-bet KO-mice as an experimental model of asthma.MethodsLung slices of 100 to 200 microm thickness were obtained from T-bet KO- and wild-type mice. Airway contraction in response to acetylcholine (ACH) was measured by video-microscopy and Ca2+-signaling in single ASMC of lung slices was assessed using two-photon-microscopy.ResultsAirways from T-bet KO-mice showed increased baseline airway tone (BAT) and BHR compared to wild-type mice. This could be mimicked by incubation of lung slices from wild-type mice with IL-13. The increased BAT was correlated with an increased incidence of spontaneous changes in intracellular Ca2+-concentrations, whereas BHR correlated with higher ACH-induced Ca2+-transients and an increased proportion of ASMC showing Ca2+-oscillations. Emptying intracellular Ca2+-stores using caffeine or cyclopiazonic acid induced higher Ca2+-elevations in ASMC from T-bet KO- compared to wild-type mice.ConclusionAltered Ca2+-homeostasis of ASMC contributes to increased BAT and BHR in lung slices from T-bet KO-mice as a murine asthma model. We propose that a higher Ca2+-content of the intracellular Ca2+-stores is involved in the pathophysiology of these changes.

| S-EPMC1395308 | biostudies-literature

TSG knock out in hiPSCs

Project description:We will perform RNAseq to evaluate the effects of the loss of a list of TSGs on the transcriptome.

| EGAS00001002262 | EGA

Knock-out of TERMINAL FLOWER 1 genes altered flowering time and plant architecture in Brassica napus.

Project description:BackgroundTERMINAL FLOWER 1 (TFL1) is a member of phosphatidylethanolamine-binding protein (PEBP) family, which plays an important role in the determination of floral meristem identity and regulates flowering time in higher plants.ResultsFive BnaTFL1 gene copies were identified in the genome of Brassica napus. The phylogenetic analysis indicated that all five BnaTFL1 gene copies were clustered with their corresponding homologous copies in the ancestral species, B. rapa and B. oleracea. The expression of the BnaTFL1s were confined to flower buds, flowers, seeds, siliques and stem tissues and displayed distinct expression profiles. Knockout mutants of BnaC03.TFL1 generated by CRISPR/Cas9 exhibited early flowering phenotype, while the knockout mutants of the other gene copies had similar flowering time as the wild type. Furthermore, knock-out mutants of individual BnaTFL1 gene copy displayed altered plant architecture. The plant height, branch initiation height, branch number, silique number, number of seeds per silique and number of siliques on the main inflorescence were significantly reduced in the BnaTFL1 mutants.ConclusionsOur results indicated that BnaC03.TFL1 negatively regulates flowering time in B. napus. BnaC03.TFL1 together with the other BnaTFL1 paralogues are essential for controlling the plant architecture.

| S-EPMC7236879 | biostudies-literature

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