Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.
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ABSTRACT:
SUBMITTER: Abulizi A
PROVIDER: S-EPMC7679013 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genome-scale metabolic reconstructions provide a biologically meaningful mechanistic basis for the genotype-phenotype relationship. The global human metabolic network, termed Recon 1, has recently been reconstructed allowing the systems analysis of human metabolic physiology and pathology. Utilizing high-throughput data, Recon 1 has recently been tailored to different cells and tissues, including the liver, kidney, brain, and alveolar macrophage. These models have shown utility in the study of systems medicine. However, no integrated analysis between human tissues has been done.To describe tissue-specific functions, Recon 1 was tailored to describe metabolism in three human cells: adipocytes, hepatocytes, and myocytes. These cell-specific networks were manually curated and validated based on known cellular metabolic functions. To study intercellular interactions, a novel multi-tissue type modeling approach was developed to integrate the metabolic functions for the three cell types, and subsequently used to simulate known integrated metabolic cycles. In addition, the multi-tissue model was used to study diabetes: a pathology with systemic properties. High-throughput data was integrated with the network to determine differential metabolic activity between obese and type II obese gastric bypass patients in a whole-body context.The multi-tissue type modeling approach presented provides a platform to study integrated metabolic states. As more cell and tissue-specific models are released, it is critical to develop a framework in which to study their interdependencies.
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Project description:Sepsis is a life threatening condition which produces multi-organ dysfunction with profound circulatory and cellular derangements. Administration of E.Coli endotoxin (LPS) produces systemic inflammatory effects of sepsis including disruption of endothelial barrier, and if severe enough death. Whole body periodic acceleration (pGz) is the headward-footward motion of the body. pGz has been shown to induce pulsatile shear stress to the endothelium, thereby releasing vascular and cardio protective mediators. The purpose of this study was to determine whether or not pGz performed as a pre-treatment or post-treatment strategy improves survival in a lethal murine endotoxin model.This study was designed as a prospective randomized controlled study in mice. pGz was performed in mice as pre-treatment (pGz-LPS, 3 days prior to LPS), post-treatment (LPS- pGz, 30 min after LPS) strategies or Control (LPS-CONT), in a lethal murine model of endotoxemia. Endotoxemia was induced with intraperitoneal injection of E.Coli LPS (40mg/kg). In a separate group of mice, a nonspecific nitric oxide synthase inhibitor (L-NAME) was provided in their drinking water and pGz-LPS and LPS-pGz performed to determine the effect of nitric oxide (NO) inhibition on survival. In another subset of mice, micro vascular leakage was determined. Behavioral scoring around the clock was performed in all mice at 30 min intervals after LPS administration, until 48 hrs. survival or death. LPS induced 100% mortality in LPS-CONT animals by 30 hrs. In contrast, survival to 48 hrs. occurred in 60% of pGz-LPS and 80% of LPS-pGz. L-NAME abolished the survival effects of pGz. Microvascular leakage was markedly reduced in both pre and post pGz treated animals and was associated with increased tyrosine kinase endothelial-enriched tunica interna endothelial cell kinase 2 (TIE2) receptor and its phosphorylation (p-TIE2). In a murine model of lethal endotoxemia, pGz performed as a pre or post treatment strategy significantly improved survival, and markedly reduced microvascular leakage. The effect was modulated, in part, by NO since a non-selective inhibitor of NO abolished the pGz survival effect.
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Project description:Prolonged immobilization from a critical illness can result in significant muscle atrophy. Whole-body vibration (WBV) could potentially attenuate the issue of muscle atrophy; however, there exists no device that could potentially provide WBV in supine position that is suitable for critically ill patients. Hence, the purpose of this study was to develop a new wearable suit, called therapeutic vibration device (TVD), that can provide WBV in supine position and test its effects on physiologic markers of physical activity including muscle activation, oxygen consumption (VO2), and regional hemoglobin oxygen saturation (rSO2). The prototype TVD delivered multi-frequency WBV axially to 19 healthy participants in supine position for 10 minutes simultaneously at 25 Hz/4.2 grms on the feet and 15 Hz/0.7 grms on the shoulders. Muscle activation was recorded by electromyography (EMG), VO2 was measured by indirect calorimetry and rSO2 was recorded by near-infrared spectroscopy. Recordings were collected from each participant from multiple body locations, on three separate days, at baseline and during the intervention. Acceleration was also recorded to gain insight into transmissibility and coherence. Repeated-measures ANOVA using Bonferroni correction revealed that the muscle activity significantly increased by 4% - 62% (p < 0.05), VO2 improved by 22.3% (p < 0.05) and rSO2 increased by 1.4% - 4.5% (p < 0.05) compared to baseline. WBV provided by the TVD is capable of producing physiologic responses consistent with mild physical activity. Such effects could potentially be valuable as an adjunct to physical therapy for early mobilization to prevent atrophy occurring from prolonged immobilization.
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Project description:The recognition that oxidative stress is a major component of several chronic diseases has engendered numerous trials of antioxidant therapies with minimal or no direct benefits. Nanomolar quantities of nitric oxide released into the circulation by pharmacologic stimulation of eNOS have antioxidant properties but physiologic stimulation as through increased pulsatile shear stress of the endothelium has not been assessed. The present study utilized a non-invasive technology, periodic acceleration (pGz) that increases pulsatile shear stress such that upregulation of cardiac eNOS occurs, We assessed its efficacy in normal mice and mouse models with high levels of oxidative stress, e.g. Diabetes type 1 and mdx (Duchene Muscular Dystrophy). pGz increased protein expression and upregulated eNOS in hearts. Application of pGz was associated with significantly increased expression of endogenous antioxidants (Glutathioneperoxidase-1(GPX-1), Catalase (CAT), Superoxide, Superoxide Dismutase 1(SOD1). This led to an increase of total cardiac antioxidant capacity along with an increase in the antioxidant response element transcription factor Nrf2 translocation to the nucleus. pGz decreased reactive oxygen species in both mice models of oxidative stress. Thus, pGz is a novel non-pharmacologic method to harness endogenous antioxidant capacity.
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Project description:BACKGROUND:Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that increases the cardiovascular risk. Regular physical exercise can promote benefits, but the MetS individuals are demotivated to perform it. Thus, new possibilities are important as an alternative intervention. The whole-body vibration can be considered an exercise modality and would be a safe and low-cost strategy to improve functional parameters of individuals in different clinical conditions. The aim of this exploratory study was to assess effects of whole-body vibration on functional parameters of MetS individuals. The hypothesis of this work was that the whole-body vibration could improve the functionality of MetS individuals. METHODS:Twenty-two individuals performed the intervention. The vibration frequency varied from 5 to 14?Hz and the peak-to-peak displacements, from 2.5 to 7.5?mm. Each session consisted of one minute-bout of working time followed by a one minute-bout of passive rest in each peak-to-peak displacement for three-times. The whole-body vibration protocol was applied twice per week for 5?weeks. Data from the trunk flexion, gait speed, sit-to-stand test and handgrip strength were collected. Physiological parameters (blood pressure and heart rate) were also evaluated. The Wilcoxon Rank test and Student t-test were used. RESULTS:No significant changes (p?>?0.05) were observed in physiological parameters (arterial blood pressure and heart rate). Significant improvements were found in trunk flexion (p?= 0.01), gait speed (p?= 0.02), sit-to-stand test (p?= 0.005) and handgrip strength (p?= 0.04) after the whole-body vibration. CONCLUSIONS:In conclusion, whole-body vibration may induce biological responses that improve functional parameters in participants with MetS without interfering in physiological parameters, comparing before and after a 5-week whole-body vibration protocol. TRIAL REGISTRATION:Register in the Registro Brasileiro de Ensaios Clínicos (ReBEC) with the number RBR 2bghmh (June 6th, 2016) and UTN: U1111-1181-1177. (virgula).
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2015-10-15 | GSE66556 | GEO
Project description:Pancreatic beta-cells couple the oxidation of glucose to the secretion of insulin. Apart from the canonical K(ATP)-dependent glucose-stimulated insulin secretion (GSIS), there are important K(ATP)-independent mechanisms involving both anaplerosis and mitochondrial GTP (mtGTP). How mtGTP that is trapped within the mitochondrial matrix regulates the cytosolic calcium increases that drive GSIS remains a mystery. Here we have investigated whether the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) is the GTPase linking hydrolysis of mtGTP made by succinyl-CoA synthetase (SCS-GTP) to an anaplerotic pathway producing phosphoenolpyruvate (PEP). Although cytosolic PEPCK (PEPCK-C) is absent, PEPCK-M message and protein were detected in INS-1 832/13 cells, rat islets, and mouse islets. PEPCK enzymatic activity is half that of primary hepatocytes and is localized exclusively to the mitochondria. Novel (13)C-labeling strategies in INS-1 832/13 cells and islets measured substantial contribution of PEPCK-M to the synthesis of PEP. As high as 30% of PEP in INS-1 832/13 cells and 41% of PEP in rat islets came from PEPCK-M. The contribution of PEPCK-M to overall PEP synthesis more than tripled with glucose stimulation. Silencing the PEPCK-M gene completely inhibited GSIS underscoring its central role in mitochondrial metabolism-mediated insulin secretion. Given that mtGTP synthesized by SCS-GTP is an indicator of TCA flux that is crucial for GSIS, PEPCK-M is a strong candidate to link mtGTP synthesis with insulin release through anaplerotic PEP cycling.
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Project description:The purpose of this investigation was to ascertain whether nitric oxide (NO) released into the circulation by a noninvasive technology called whole body periodic acceleration (WBPA) could increase mucociliary clearance (MCC). It was based on observations by others that nitric oxide donor drugs increase ciliary beat frequency of nasal epithelium without increasing mucociliary clearance. Tracheal mucous velocity (TMV), a reflection of MCC, was measured in sheep after 1-hour treatment of WBPA and repeated after pretreatment with the NO synthase inhibitor, L-NAME to demonstrated action of NO. Aerosolized human neutrophil elastase (HNE) was administered to sheep to suppress TMV as might occur in cystic fibrosis and other inflammatory lung diseases. WBPA increased TMV to a peak of 136% of baseline 1h after intervention, an effect blocked by L-NAME. HNE reduced TMV to 55% of baseline but slowing was reversed by WBPA, protection lost in the presence of L-NAME. NO released into the circulation from eNOS by WBPA can acutely access airway epithelium for improving MCC slowed in cystic fibrosis and other inflammatory lung diseases as a means of enhancing host defense against pathogens.
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