Abstract 102: Time-of-intake Regulates Glucocorticoid Pharmacology Of Cardiac Bioenergetics

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Mattia Quattrocelli ◽  
Michelle Wintzinger ◽  
Karen Miz
Keyword(s):  
Ex Vivo ◽  
Gene Knockout ◽  
Heart Tissue ◽  
Functional Coupling ◽  
Specific Gene ◽  
Heart Metabolism ◽  
Respiratory Capacity ◽  
Circadian Time ◽  
The Impact ◽  
Mitochondrial Respiratory

Glucocorticoid steroids are circadian regulators of energy balance. However, the specific direct effects of glucocorticoids on heart metabolism remain unresolved. Moreover, the impact of circadian time-of-intake on glucocorticoid pharmacology is still unknown. Here, we investigated whether circadian time of exposure gates the effects of synthetic glucocorticoids on heart bioenergetics. We compared the effects of diurnal versus nocturnal glucocorticoids in heart tissue and mitochondria from wildtype mice, controlling the subjective circadian time of drug injection. To avoid interferences from other tissues, we developed an ex vivo system to interrogate the mitochondrial respiratory capacity rate (state III/state IV) in isolated hearts. We found that diurnal but not nocturnal pulse of the glucocorticoid prednisone increased the mitochondrial respiratory capacity rate in heart. This correlated with circadian-restricted effects on mitochondrial abundance. This was remarkable as it contrasts the circadian fluctuations of endogenous glucocorticoids. Using transgenic mice with inducible cardiac-specific gene knockout, we found that the bioenergetic effects of diurnal-restricted prednisone were dependent on the glucocorticoid receptor and its co-factor Kruppel-like factor 15. Considering the bioenergetic decline that hallmarks the aging heart, we asked whether these circadian-gated effects were applicable to aged mice. We therefore treated 24 months-old mice for 12 weeks with a diurnal-restricted regimen of prednisone. Compared to vehicle, diurnal prednisone increased mitochondrial respiration along with NAD + and ATP content in aged hearts. Moreover, lipidomic profiling of myocardial tissue showed that the vast majority of lipids were downregulated after treatment, including triacylglycerols, suggesting a functional coupling between lipid utilization and mitochondrial oxidation in treated hearts. We also found that diurnal-restricted prednisone rescued bioenergetics and improved function in diabetic hearts from db/db mice. In summary, our data indicate that glucocorticoids regulate cardiac bioenergetics according to circadian-time of intake, supporting a role for chrono-pharmacology in aged and diabetic hearts.

scholarly journals Exercise training improves vascular mitochondrial function

2016 ◽  
Vol 310 (7) ◽  
pp. H821-H829 ◽  
Author(s):  
Song-Young Park ◽  
Matthew J. Rossman ◽  
Jayson R. Gifford ◽  
Leena P. Bharath ◽  
Johann Bauersachs ◽  
...  
Keyword(s):  
Exercise Training ◽  
Vascular Function ◽  
Respiratory Function ◽  
Complex I ◽  
Citrate Synthase ◽  
Reactive Oxygen Species Generation ◽  
Redox Balance ◽  
Respiratory Capacity ◽  
The Impact ◽  
Mitochondrial Respiratory

Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1, isocitrate dehydrogenase ( Idh) 2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser1177), and suppressed reactive oxygen species generation (all P < 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function.

scholarly journals A55 INVESTIGATING THE ROLE OF ENDOGENOUS INTERLEUKIN-10 IN INTESTINAL EPITHELIAL CELLS AND HOMEOSTASIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 12-13
Author(s):  
H D Nguyen ◽  
A Stadnyk
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelium ◽  
Ex Vivo ◽  
Gene Knockout ◽  
Immunofluorescent Staining ◽  
Absorptive Cell ◽  
Small Intestinal Epithelium ◽  
Basolateral Side ◽  
Small Intestinal ◽  
The Impact

Abstract Background IL-10 is appreciated for its potent anti-inflammatory effects on leukocytes in mucosal immunity. However, far less attention has been paid to the impact of IL-10 on epithelial cells, which make up the crucial barrier interface between the host mucosa and the external environment. Furthermore, most studies examine the effects of exogenous IL-10, disregarding the possible presence and function of autocrine or paracrine IL-10 in the epithelium. Aims Using ex vivo organoids we aimed to examine the small intestinal epithelium for IL-10 and dissect any role for endogenously produced cytokine. Methods We growed small intestinal organoids (enteroids) from crypts isolated from C57BL/6 mice (WT) and IL-10-gene knockout mice (IL-10KO). Cellular markers were characterized through qpCR, while IL-10 and IL-10 receptor localization was characterized though immunofluorescence. Results We discovered that cells in WT enteroids expressed IL-10 and IL-10R1 constitutively throughout development. Immunofluorescent staining revealed that IL-10 localizes to Paneth cells and appears to be secreted apically. Having established that IL-10 is secreted in enteroids, we compared enteroids from IL-10KO versus WT mice. IL-10KO enteroids developed to morphologically resemble WT enteroids; however, we detected an imbalance with lower secretory cell markers over absorptive cell types in the IL-10KO enteroids, measured as less mRNA for lysozyme, cryptdins and mucin-2. Addition of IL-10 to IL-10KO enteroids did not correct these defects, but did ameliorate the lineage balance by reducing absorptive cell lineage markers (sucrose isomaltase). IL-10R1 was localized on both apical and basolateral side of cell in enteroids. We suspect that epithelial-derived IL-10 likely acts on apical IL-10R, which may conduct a different response from basolateral receptor stimulation. Conclusions In conclusion, IL-10 is present in the small intestinal epithelium; more remains to be determined regarding the role this cytokine plays in gut development and homeostasis. Funding Agencies NSERC

scholarly journals Vascular mitochondrial respiratory function: the impact of advancing age

2018 ◽  
Vol 315 (6) ◽  
pp. H1660-H1669 ◽  
Author(s):  
Soung Hun Park ◽  
Oh Sung Kwon ◽  
Song-Young Park ◽  
Joshua C. Weavil ◽  
Robert H. I. Andtbacka ◽  
...  
Keyword(s):  
Oxidative Coupling ◽  
Respiratory Function ◽  
Complex I ◽  
Coupling Efficiency ◽  
Middle Aged ◽  
Mitochondrial Content ◽  
Respiratory Capacity ◽  
Age Related ◽  
The Impact ◽  
Mitochondrial Respiratory

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s−1·mg−1 and CI+II: 12.4 ± 0.8 pmol·s−1·mg−1, P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s−1·mg−1 and CI+II: 8.3 ± 0.5 pmol·s−1·mg−1) and old (CI: 7.2 ± 0.4 pmol·s−1·mg−1 and CI+II: 7.6 ± 0.5 pmol·s−1·mg−1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = −0.56 (CI), r = −0.7 (CI+II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = −0.71, P < 0.05). As CS activity was inversely correlated with age ( r = −0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s−1·mg−1·U CS−1, P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s−1·mg−1·U CS−1, respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.

Impaired mitochondrial function in chronically ischemic human heart

2013 ◽  
Vol 304 (11) ◽  
pp. H1407-H1414 ◽  
Author(s):  
Nis Stride ◽  
Steen Larsen ◽  
Martin Hey-Mogensen ◽  
Christina N. Hansen ◽  
Clara Prats ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Human Heart ◽  
Ex Vivo ◽  
Ischemic Myocardium ◽  
Acute Ischemia ◽  
Ros Production ◽  
Respiratory Capacity ◽  
Mitochondrial Respiratory

Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. Furthermore, ischemic damage may cause excessive production of reactive oxygen species (ROS), producing mitochondrial damage, hereby reinforcing a vicious circle. Ischemic preconditioning has been proven protective in acute ischemia, but the subject of chronic ischemic preconditioning has not been explored in humans. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared with nonischemic myocardium ( P < 0.05), but the degree of coupling (respiratory control ratio) did not differ ( P > 0.05). The presence of ex vivo hypoxia did not reveal any chronic ischemic preconditioning of the ischemic myocardial regions ( P > 0.05). ROS production was higher in ischemic myocardium ( P < 0.05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found.

scholarly journals Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats

2020 ◽  
Vol 318 (2) ◽  
pp. E216-E223 ◽  
Author(s):  
Robert W. McGarrah ◽  
Guo-Fang Zhang ◽  
Bridgette A. Christopher ◽  
Yann Deleye ◽  
Jacquelyn M. Walejko ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Transporter ◽  
Heart Tissue ◽  
Chow Diet ◽  
Restricted Diet ◽  
Hexokinase Ii ◽  
Acetyl Coa ◽  
Heart Metabolism ◽  
Branched Chain ◽  
The Impact

Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.

High aerobic exercise capacity predicts increased mitochondrial response to exercise training

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Schwarzer ◽  
S Zeeb ◽  
E Heyne ◽  
L.G Koch ◽  
S.L Britton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Respiratory Capacity ◽  
The Impact ◽  
Mitochondrial Respiratory

Abstract   Low exercise capacity is a strong predictor of all-cause cardiovascular mortality and morbidity. In contrast, high exercise capacity is protective and “physical fitness” is considered beneficial. These effects seem to be mediated through mitochondrial function. Importantly, exercise capacity consists of an intrinsic (genetic) and an extrinsic (exercise, environmental) part. In humans, these two parts cannot be truly separated. The rat model of high (HCR) and low (LCR) capacity runners allows to distinguish between the two parts. We assessed mitochondrial function in this model, specifically investigating the impact of exercise training on mitochondrial respiratory capacity. HCR and LCR were divided into control and exercised groups. Exercise capacity was determined individually using a ramped test. Animals were trained five times a week for four weeks on a treadmill. Mitochondria were isolated from heart, M. gastrocnemius and liver. Citrate synthase activity and protein content were determined photometrically and respiratory capacity was measured using a Clark-type electrode. At the same age and tibia length, LCR-C were heavier and had a lower heart to body weight ratio than HCR-C. Citrate synthase activity was lower in skeletal muscle of LCR but cardiac citrate synthase was not different between sedentary HCR and LCR. Respiratory capacity in heart and liver was not different between sedentary HCR and LCR but was lower in skeletal muscle in LCR compared to HCR with all selected substrates (glutamate: 86,0±17,6 vs. 63,7±8,0; succinate: 203±19 vs. 136±17 nAO/min/mg Protein). Exercise training led to an increase in body weight in HCR but did not change body weight in LCR. Similarly, gastrocnemius and soleus weights only increased with exercise in HCR. Exercise led to an increase in citrate synthase activity in hearts of HCR (0,78±0,07 vs. 1,58±0,45 U/mg Protein) but not of LCR. Consistently, mitochondrial respiratory capacity was found increased in HCR with exercise in heart with all substrates (glutamate: 261±43 vs. 305±35; succinate 417±32 vs. 539±65 nAO/min/mg Protein). Liver was not affected by exercise. Conclusion Our data suggest that genetic predisposition for aerobic capacity additionally affects the response of mitochondria to exercise. Thus, it may be possible that the “born runner” benefits more from aerobic exercise training than the “less genetically equipped counterpart”. Funding Acknowledgement Type of funding source: None

scholarly journals Modulation of Human Mesenchymal Stem Cells by Electrical Stimulation Using an Enzymatic Biofuel Cell

Catalysts ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Won-Yong Jeon ◽  
Seyoung Mun ◽  
Wei Beng Ng ◽  
Keunsoo Kang ◽  
Kyudong Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Electrical Stimulation ◽  
Regenerative Medicine ◽  
Cell Morphology ◽  
Electrical Current ◽  
Specific Gene ◽  
Next Generation ◽  
The Impact

Enzymatic biofuel cells (EBFCs) have excellent potential as components in bioelectronic devices, especially as active biointerfaces to regulate stem cell behavior for regenerative medicine applications. However, it remains unclear to what extent EBFC-generated electrical stimulation can regulate the functional behavior of human adipose-derived mesenchymal stem cells (hAD-MSCs) at the morphological and gene expression levels. Herein, we investigated the effect of EBFC-generated electrical stimulation on hAD-MSC cell morphology and gene expression using next-generation RNA sequencing. We tested three different electrical currents, 127 ± 9, 248 ± 15, and 598 ± 75 nA/cm2, in mesenchymal stem cells. We performed transcriptome profiling to analyze the impact of EBFC-derived electrical current on gene expression using next generation sequencing (NGS). We also observed changes in cytoskeleton arrangement and analyzed gene expression that depends on the electrical stimulation. The electrical stimulation of EBFC changes cell morphology through cytoskeleton re-arrangement. In particular, the results of whole transcriptome NGS showed that specific gene clusters were up- or down-regulated depending on the magnitude of applied electrical current of EBFC. In conclusion, this study demonstrates that EBFC-generated electrical stimulation can influence the morphological and gene expression properties of stem cells; such capabilities can be useful for regenerative medicine applications such as bioelectronic devices.

scholarly journals 231 Impact of Brachyspira hyodysentariae on intestinal function and integrity

2020 ◽  
Vol 98 (Supplement_3) ◽  
pp. 116-116
Author(s):  
Emma T Helm ◽  
Susanne J Lin ◽  
Nicholas Gabler ◽  
Eric R Burrough
Keyword(s):  
Ex Vivo ◽  
Potato Starch ◽  
Nutrient Digestibility ◽  
High Morbidity ◽  
Post Inoculation ◽  
Intestinal Function ◽  
Treatment Groups ◽  
Intestinal Integrity ◽  
Beet Pulp ◽  
The Impact

Abstract Swine dysentery (SD) induced by Brachyspira hyodysentariae (Bhyo) causes colitis and mucohemorrhagic diarrhea in grow-finish pigs, however little is known about the physiological changes that occur to the gastrointestinal tract during Bhyo infection. Thus, the objective of this study was to evaluate the impact of a Bhyo challenge on intestinal function and integrity of pigs fed two divergent diets. A total of 36 Bhyo negative gilts (24.3 ± 3.6 kg BW) were selected and assigned to one of three treatment groups (n=12 pigs/trt): 1) Bhyo negative, 20% DDGS diet (CON), 2) Bhyo challenged, 20% DDGS diet (DDGS), and 3) Bhyo challenged, 10% DDGS, 5% beet pulp and 5% resistant potato starch diet (RS). Pigs were fed diets 21 days prior to challenge and on days post inoculation (dpi) 0 and 1, pigs were inoculated with Bhyo or sham. Fecal samples were collected for ATTD and pigs were euthanized for colon collection within 72 hours of initial observation of clinical SD, or at the end of the study (dpi 10-16). Tissues were assessed for ex vivo measures of intestinal integrity and mitochondrial function. The challenge resulted in high morbidity, with 88% of DDGS and RS pigs developing clinical SD. Colon transepithelial resistance was increased in DDGS pigs compared with CON and RS pigs (P=0.005), and colon macromolecule permeability was reduced in both DDGS and RS pigs compared with CON pigs (P=0.006), likely due to mucoid discharge. Colonic mitochondrial oxygen consumption was not impacted by treatment (P &gt;0.10). Further, ATTD of DM, OM, N, and GE were reduced in DDGS pigs compared with CON pigs (P&lt; 0.001), whilst nutrient digestibility was not reduced in RS pigs. Taken together, these data show Bhyo does not appear to reduce ex vivo colonic integrity. Further, the RS diet may reduce severity of a Bhyo challenge.

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