Biogenesis In Heart Research Articles

Far Forward Gaps in Hemorrhagic Shock and Prolonged Field Care: An Update of ALM Fluid Therapy for Field Use.

Future expeditionary missions are expected to occur in more remote austere environments where combat medics and casualties may have to wait up to 7 days before resupply or safe evacuation. Currently, there is no effective fluid therapy for hemorrhagic shock (HS) at the point-of-injury and continuum-of-care over this extended period. We have been developing a small-volume IV or IO ALM therapy for noncompressible HS and have shown in preclinical models that it extends survival to 3 days, reduces abdominal bleeding by 60%, blunts inflammation, corrects coagulopathy, preserves platelet function, and prevents immunodeficiency. The ALM-survival phenotype is associated with an upregulation of the master genes of metabolism and mitochrondrial biogenesis in heart and brain and a downregulation in the periphery. Future translational studies will investigate the timing and nature of the "switch" and extend survival to 7 days. We will also discuss some of the controversies of ALM resuscitation in pigs, present our Systems Hypothesis of Trauma (SHOT), and discuss future clinical safety trials before field use.

Influence of maternal protein malnutrition on oxidative stress and regulators of mitochondrial biogenesis in female rat hearts over succeeding generations

AimsWe sought to evaluate the effects of maternal protein restriction (LP) on oxidative balance and transcription factors for mitochondrial biogenesis in the hearts of young female rats of both the first (F1) and second (F2) generation. Main methodsWe evaluated oxidative stress biomarkers (lipid peroxidation and protein oxidation), enzymatic antioxidant defense (activity of superoxide dismutase-SOD, catalase, and glutathione-S-transferase-GST), nonenzymatic antioxidant defense (reduced glutathione-GSH and sulfhydryl groups) and gene expression of AMPK, PGC-1α and TFAM. Key findingsInterestingly, lipid peroxidation was decreased (49%, p < 0.001) in the LP-F1 group and 59% (p < 0.001) in LP-F2. In enzymatic defense, we observed increases in SOD activity in the LP-F1 group (79%, p = 0.036) and in CAT activity (approximately 40%, p = 0.041). GSH was increased in F2 in both groups (LP 546%, p < 0.0001 and in NP 491.7%, p < 0.0001). With respect to mitochondrial biogenesis gene transcription, we observed a decrease in AMPK (60%, p < 0. 0001) and an increase in PGC-1α (340%, p < 0.001) in LP compared to NP in the F1 generation. TFAM was decreased in LP-F2L compared to NP-F2L (42%, p = 0.0069) and increased in LP-F2 compared to LP-F1 (160%, p = 0.0037). SignificanceOur study contributes to knowledge of inheritance, showing that despite the potential mitochondrial ‘inheritance’ of cardiovascular damage caused by maternal malnutrition, that damage is not cross-generational and can be eliminated with proper nutrition in the F1 generation.

The effect of apelin-13 on pancreatic islet beta cell mass and myocardial fatty acid and glucose metabolism of experimental type 2 diabetic rats

Apelin, a new identified adipokine, and its G protein–coupled receptor named APJ are widely expressed in various tissues. Apelin has been found to play important roles in the physiopathology of multiple diseases. Our aim is to assess the effect of long-term apelin treatment on serum insulin level and pancreatic islet beta-cell mass in the late stage of type 2 diabetes without hyperinsulinemia and to investigate the role of apelin in myocardial fatty acid and glucose metabolism. In the present study, the high-fat diet fed-streptozotocin-induced experimental type 2 diabetic rats were given once daily intraperitoneal injection of apelin-13 (0.1 μmol/kg) for 10 weeks. We observed that apelin significantly improved serum insulin reduction and reduced hyperglycemia. Histologic analysis showed that long-term apelin treatment significantly increased pancreatic islet beta cell mass. Exogenous apelin failed to change dyslipidaemia of type 2 diabetic rats. Apelin treatment markedly decreased elevated myocardial FFA and glycogen content. Treatment of type 2 diabetic rats with apelin markedly reduced increased gene expressions of the cardiac fatty acid transporter CD36, CPT-1, and Peroxisome proliferator-activated receptor (PPAR)-α. Whereas the gene levels of citrate synthase and peroxisome proliferator–activated receptor γ coactivator 1-α (PGC1-α), a transcriptional coactivator, mediating mitochondrial biogenesis in heart were unaltered in response to exogenous apelin. Taken together, longer-term apelin treatment prevented pancreatic beta-cell loss or failure in experimental type 2 diabetic rats. Apelin can regulate myocardial metabolism. Apelin reduced myocadial fatty acid uptake and oxidation through inhibiting PPAR-α but did not affect myocardial mitochondrial biogenesis in type 2 diabetic rats.

Maternal exercise upregulates mitochondrial gene expression and increases enzyme activity of fetal mouse hearts.

Maternal exercise during pregnancy has been shown to improve the long‐term health of offspring in later life. Mitochondria are important organelles for maintaining adequate heart function, and mitochondrial dysfunction is linked to cardiovascular disease. However, the effects of maternal exercise during pregnancy on mitochondrial biogenesis in hearts are not well understood. Thus, the purpose of this study was to test the hypothesis that mitochondrial gene expression in fetal myocardium would be upregulated by maternal exercise. Twelve‐week‐old female C57BL/6 mice were divided into sedentary and exercise groups. Mice in the exercise group were exposed to a voluntary cage‐wheel from gestational day 1 through 17. Litter size and individual fetal weights were taken when pregnant dams were sacrificed at 17 days of gestation. Three to four hearts from the same group were pooled to study gene expression, protein expression, and enzyme activity. There were no significant differences in litter size, sex distribution, and average fetal body weight per litter between sedentary and exercised dams. Genes encoding mitochondrial biogenesis and dynamics, including nuclear respiratory factor‐1 (Nrf1), Nrf2, and dynamin‐related GTPase termed mitofusin‐2 (Mfn2) were significantly upregulated in the fetal hearts from exercised dams. Cytochrome c oxidase activity and ATP production were significantly increased, while the hydrogen peroxide level was significantly decreased in the fetal hearts by maternal exercise. Our results demonstrate that maternal exercise initiated at day 1 of gestation could transfer the positive mitochondrial phenotype to fetal hearts.

Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS(-/-) mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport.

G protein coupled receptor kinase 2 interacting protein 1 (GIT1) is a novel regulator of mitochondrial biogenesis in heart

G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multi-function scaffold protein. However, little is known about its physiological role in the heart. Here we sought to identify the cardiac function of GIT1. Global GIT1 knockout (KO) mice were generated and exhibited significant cardiac hypertrophy that progressed to heart failure. Electron microscopy revealed that the hearts of GIT1 KO mice demonstrated significant morphological abnormities in mitochondria, including decreased mitochondrial volume density, cristae density and increased vacuoles. Moreover, mitochondrial biogenesis-related gene peroxisome proliferator-activated receptor γ (PPARγ) co-activator-1α (PGC-1α), PGC-1β, mitochondrial transcription factor A (Tfam) expression, and total mitochondrial DNA were remarkably decreased in hearts of GIT1 KO mice. These animals also had impaired mitochondrial function, as evidenced by reduced ATP production and dissipated mitochondrial membrane potential (Ψ m) in adult cardiomyocytes. Concordant with these mitochondrial observations, GIT1 KO mice showed enhanced cardiomyocyte apoptosis and cardiac dysfunction. In conclusion, our findings identify GIT1 as a new regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation.

Mitochondrial Oxidative Stress Mediates Angiotensin II–Induced Cardiac Hypertrophy and Gαq Overexpression–Induced Heart Failure

Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood. We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes. Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of angiotensin II-treated mice. The causal role of mitochondrial ROS in angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase γ, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure. These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.

Does calorie restriction induce mitochondrial biogenesis? A reevaluation

It has been reported that 30% calorie restriction (CR) for 3 mo results in large increases in mitochondrial biogenesis in heart, brain, liver, and adipose tissue, with concomitant increases in respiration and ATP synthesis. We found these results surprising, and performed this study to determine whether 30% CR does induce an increase in mitochondria in heart, brain, liver, adipose tissue, and/or skeletal muscle. To this end, we measured the levels of a range of mitochondrial proteins, and mRNAs. With the exception of long-chain acyl-CoA dehydrogenase protein level, which was increased ∼60% in adipose tissue, none of the mitochondrial proteins or mRNAs that we measured were increased in rats subjected to 30% CR for 14 wk. There was also no increase in citrate synthase activity. Because it is not possible to have an increase in mitochondria without any increase in key mitochondrial proteins, we conclude that 30% CR does not induce an increase in mitochondria in heart, brain, liver, adipose tissue, or skeletal muscle in laboratory rodents.