Myocardial Glycogen Research Articles

Comparison between Myocardial Glycogen Storage in CABG after Using Blood Cardioplegia versus HTK Solution

Abstract Background Inadequate myocardial protection in long ischaemic periods followed by reperfusion is an issue of concern in cardiac surgery. Cardioplegic solutions improve the tolerance to ischaemia and reperfusion by preserving myocardial energy reserves, preventing osmotic and electrolyte imbalances and buffering acidosis. Objective This somewhat surprising given the high number of procedures performed worldwide with this cardioplegic solution. As such, the purpose of this study was to assess the safety of the HTK solution when compared with our standard blood cardioplegia in coronary artery bypass graft operations via assessment of myocardial glycogen storage. Patients and Methods This was a retrospective, convenient, non- randomized study conducted on 40 consecutive patients who underwent isolated elective CABG at department of cardiothoracic surgery at Ain Shams University Hospitals. The aim of the study was to compare early outcomes of Custodiol versus blood cardioplegia in coronary artery bypass graft surgery via assessment of glycogen storage in myocarduim via assessment of myocardial glycogen storage. at Ain Shams University Hospitals. Results There was no statistically significant difference between the two groups of myocardial glycogen storage post-operative. Conclusion There was statistically significant difference between the pre and post-operative in both custodial and blood cardioplegia. There was no statistically significant difference between the two groups of myocardial protection in mortality and morbidity. Custodiol cardioplegia is an easy technique and simple without need of preparation or repeated administration.

Impaired cardiac glycolysis and glycogen depletion are linked to poor myocardial outcomes in juvenile male swine with metabolic syndrome and ischemia.

Obesity continues to rise in the juveniles and obese children are more likely to develop metabolic syndrome (MetS) and related cardiovascular disease. Unfortunately, effective prevention and long-term treatment options remain limited. We determined the juvenile cardiac response to MetS in a swine model. Juvenile male swine were fed either an obesogenic diet, to induce MetS, or a lean diet, as a control (LD). Myocardial ischemia was induced with surgically placed ameroid constrictor on the left circumflex artery. Physiological data were recorded and at 22 weeks of age the animals underwent a terminal harvest procedure and myocardial tissue was extracted for total metabolic and proteomic LC/MS-MS, RNA-seq analysis, and data underwent nonnegative matrix factorization for metabolic signatures. Significantly altered in MetS versus. LD were the glycolysis-related metabolites and enzymes. In MetS compared with LD Glycogen synthase 1 (GYS1)-glycogen phosphorylases (PYGM/PYGL) expression disbalance resulted in a loss of myocardial glycogen. Our findings are consistent with the concept that transcriptionally driven myocardial changes in glycogen and glucose metabolism-related enzymes lead to a deficiency of their metabolite products in MetS. This abnormal energy metabolism provides insight into the pathogenesis of the juvenile heart in MetS. This study reveals that MetS and ischemia diminishes ATP availability in the myocardium via altering the glucose-G6P-pyruvate axis at the level of metabolites and gene expression of related enzymes. The observed severe glycogen depletion in MetS coincides with disbalance in expression of GYS1 and both PYGM and PYGL. This altered energy substrate metabolism is a potential target of pharmacological agents for improving juvenile myocardial function in MetS and ischemia.

On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-β-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11mM [5-3 H]glucose and/or 4mM [14 C]βHB to measure glycolytic rates or βHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reaction, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi ) concentrations were measured using 31 P-nuclear magnetic resonance spectroscopy. Rates of βHB oxidation in LG hearts were half that in HG hearts, with βHB oxidation directly proportional to glycogen content. βHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with βHB alone was twice that of hearts perfused with βHB and glucose, which had significantly higher levels of the glycolytic intermediates fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. βHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total NADP/H pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although βHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. βHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac βHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (d-β-hydroxybutyrate, acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Krebs cycle intermediates; therefore their utilisation requires anaplerotic supplementation, and intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. It is demonstrated here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate β-hydroxybutyrate oxidation in isolated perfused rat heart, and this contribution was quantified using a novel pulse-chase metabolic approach. Further, using metabolomics and 31 P-MR, it was shown that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise βHB, and βHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis.

Effects of Nanometer Hydroxyapatite Aqueous Solution on Anaerobic Motor Ability of Mice

Nanometer hydroxyapatite is a new biomaterial with development potential. Its main components are very similar to those found in animal teeth. It has good biocompatibility and bioactivity. Can be closely bound to human tissue, repair tissue. With relatively more biosorption sites, it can be used as a protein carrier as an important strategy to fight cancer or promote the efficiency of tissue repair. It is widely used in biomedical fields, such as release carrier and tissue repair. With the development of modern medicine, the performance and application of nanometer hydroxyapatite are required. The purpose of this paper is to observe the effect of nanometer hydroxyapatite hydrosol on the anaerobic exercise ability of mice, and explore the mechanism of nanometer hydroxyapatite hydrosol on the anaerobic exercise ability of mice, which is of great significance for the application of nanometer hydroxyapatite in medicine and competitive sports. In this experiment, mathematical statistics were used to analyze the anaerobic swimming exhaustion time of mice in the nanometer hydroxyapatite injection group, sodium bicarbonate injection group, distilled water injection group and blank control group. The blood lactic acid content and immediate skeletal muscle lactic acid content of mice after anaerobic exercise were determined by statistical method. Finally, big data analysis method was used to fit the data and analyze the myocardial lactic acid value, skeletal muscle glycogen content and myocardial muscle glycogen content of mice injected with nano-hydroxyapatite sol after anaerobic swimming exhaustion. The experimental data showed that after the injection of nanometer hydroxyapatite hydrosol, the movement ability of mice increased. Experimental data showed that the nanometer hydroxyapatite hydrosol could improve the anaerobic exercise ability of mice, by neutralizing the lactic acid produced by the anaerobic exercise blood cells and cardiac muscle cells of mice, and prevent the accumulation of lactic acid, thereby increasing the anaerobic exercise ability by 40%, which is of great significance for athletes' exercise guidance in competitive sports.

Up-Regulation of Glycogen Synthesis and Degradation Enzyme Level Maintained Myocardial Glycogen in Huddling Brandt's Voles Under Cool Environments.

Small mammals exhibit limited glucose use and glycogen accumulation during hypothermia. Huddling is a highly evolved cooperative behavioral strategy in social mammals, allowing adaptation to environmental cooling. However, it is not clear whether this behavior affects the utilization of glycogen in cold environments. Here, we studied the effects of huddling on myocardial glycogen content in Brandt’s voles (Lasiopodomys brandtii) under a mild cold environment (15°C). Results showed that (1) Compared to the control (22°C) group (CON), the number of glycogenosomes more than tripled in the cool separated group (CS) in both males and females; whereas the number of glycogenosomes increased in females but was maintained in males in the cool huddling group (CH). (2) Glycogen synthase (GS) activity in the CS group remained unchanged, whereas glycogen phosphorylase (GYPL) activity decreased, which mediated the accumulation of glycogen content of the CS group. (3) Both GS and GYPL activity increased which may contribute to the stability of glycogen content in CH group. (4) The expression levels of glucose transporters GLUT1 and GLUT4 increased in the CS group, accompanied by an increase in glucose metabolism. These results indicate that the reduced glycogen degradation enzyme level and enhanced glucose transport may lead to an increase in myocardial glycogen content of the separated voles under cool environment; while the up-regulation of glycogen synthesis and degradation enzyme level maintained myocardial glycogen content in the huddling vole.

STBD1 (Starch-domain-containing-binding-protein 1) Modulates Myocardial Glycogen Handling in Systemic Metabolic Challenge

Diastolic dysfunction is an early feature of some forms of heart failure. Heart failure has also been associated with aberrant myocardial glycogen handling. The underlying mechanisms of this are poorly understood. Starch-binding domain-containing-protein-1 (STBD1) binds to glycogen and acts as a chaperone protein in autophagic glycogen breakdown. Recent findings in our laboratory demonstrate that STBD1-deficient mice present lower myocardial glycogen content. The aim of this experimental study was to investigate if STBD1 manipulation could be cardioprotective in a metabolic challenge setting.

Cardiopulmonary resuscitation ameliorates myocardial mitochondrial dysfunction in a cardiac arrest rat model

PurposePrevious studies implicate that the mitochondrial injury may play an important role in the development of post-resuscitation myocardial dysfunction, however few of them are available regarding the ultrastructural alterations of myocardial mitochondria, mitochondrial energy producing and utilization ability in the stage of arrest time (no-low) and resuscitation time (low-flow). This study aimed to observe the dynamic changes of myocardial mitochondrial function and metabolic disorders during cardiac arrest (CA) and following cardiopulmonary resuscitation (CPR). MethodsA total of 30 healthy male Sprague-Dawley rats were randomized into three groups: 1) VF/CPR: Ventricular fibrillation (VF) was electrically induced, and 5 min of CPR was performed after 10 min of untreated VF; 2) Untreated VF: VF was induced and untreated for 15 min; and 3) Sham: Rats were identically prepared without VF/CPR. Amplitude spectrum area (AMSA) at VF 5, 10 and 15 min were calculated from ECG signals. The rats' hearts were quickly removed at the predetermined time of 15 min after beginning the procedure to gather measurements of myocardial mitochondrial function, high-energy phosphate stores, lactate, mitochondrial ultrastructure, and myocardial glycogen. ResultsThe mitochondrial respiratory control ratios significantly decreased after CA compared to sham group. CPR significantly increased respiratory control ratios compared with untreated VF animals. A significant decrease of myocardial glycogen was observed after CA, and a more rapid depletion of myocardial glycogen was observed in CPR animals. CPR significantly reduced the tissue lactate. The mitochondrial ultrastructure abnormalities in CPR animals were less severe than untreated VF animals. AMSA decayed during untreated VF; however, it was significantly greater in CPR group than the untreated VF group. In addition, AMSA was clearly positively correlated with ATP, but negatively correlated with myocardial glycogen. ConclusionImpairment of myocardial mitochondrial function and the incapability of utilizing glycogen were observed after CA. Furthermore, optimal CPR might, in part, preserved mitochondrial function and enhanced utilization of myocardial glycogen.

Myocardial glycogen depletion leads to improved left ventricular remodeling in a mouse MI model

High glycogen (GLN) content is generally considered deleterious in prolonged ischemia, however, the exact role of GLN during permanent myocardial infarction (MI) and left ventricular (LV) remodeling post-MI, remains poorly understood. This study aimed to investigate whether myocardial GLN depletion can attenuate adverse LV remodeling post-MI. We used a transgenic knock-in (KI) mouse, in which the allosteric pathway of GLN synthesis is inhibited in muscle, leading to dramatically suppressed myocardial GLN levels. WT and KI male mice (10–12 weeks old) were subjected to MI by left anterior descending (LAD) coronary artery permanent ligation. Heart function was measured by 2D-echo (Vevo 2100, Visualsonics). Mice were sacrificed 56 days post-MI and hearts were collected to measure myocardial GLN content and perform IHC and mRNA studies. Basal GLN content was dramatically depressed in KI hearts. We demonstrated a robustly reduced LV dilatation in KI mice 56 days post-MI, as evidenced by lower end-diastolic volume (WT: 167.69 ± 13.42 vs KI: 138.00 ± 4.62 μl; P < 0.05) and end-systolic volume (WT: 147.62 ± 14.58 vs KI: 123.15 ± 4.05 μl; P < 0.05). Moreover, KI mice exhibited attenuated global LV fibrosis (WT: 61.69 ± 11.10 vs KI: 37.42 ± 6.90%; P < 0.05) and a significant decrease in border zone fibrosis (WT: 58.59 ± 12.11 vs KI: 30.33 ± 4.94%; P < 0.05). Surprisingly, KI MI mice demonstrated a dramatic decrease in myocardial rupture incidence (WT: 40.00 vs KI: 6.25%) and improved survival 56 days post-MI (WT: 42.86% vs KI: 60%). GLN depletion in KI hearts attenuates post-MI adverse LV remodeling and improves survival compared to WT. There is a strong correlation between the reduction of cardiac remodeling and a drastic effect on fibrosis deposition, especially in the border zone. Further studies are required, in order to shed light onto the association between low GLN content, cardioprotection and fibrosis.

Abstract 289: Relationship Between Myocardial Glycogen Concentrations and Amplitude Spectrum Area During Ventricular Fibrillation in a Rat Model of Cardiac Arrest and Resuscitation

Introduction: Myocardial high-energy phosphate (ATP) levels has been demonstrated correlating with amplitude spectrum area (AMSA) during ventricular fibrillation (VF) in previous experimental studies. In the present study, we investigated the relationship between AMSA and myocardial glycogen content (MGC),which can be used to reflect the status of myocardial energy metabolism indirectly during VF. Hypothesis: AMSA has a significantly correlation with MGC during VF in a rat model of cardiac arrest and resuscitation. Methods: Twenty male Sprague-Dawley rats weighing 350 to 450 g were utilized and randomized into two groups: VF and cardiopulmonary resuscitation (CPR) (VF/CPR group) or untreated VF (VF group). 5 mins of CPR was performed after 10 mins of untreated VF in VF/CPR animals. Amplitude spectrum area (AMSA) at VF 5, 10 and 15 mins were calculated from ECG signals. The rats’ hearts were quickly removed at the predetermined time of 15 min for determines the glycogen contents by the anthrone reagent method using a glycogen assay kit. Results: AMSA values significantly decreased during untreated VF in both VF and VF/CPR animals. However, much greater AMSA during CPR was achieved by the VF/CPR group in comparison with the VF group. There was a marked and negative relationship between AMSA at VF 15 min and MGC. (Figure). Conclusion: MGC was significantly and negatively correlated with AMSA during VF in this rat model of cardiac arrest and resuscitation. In clinical practice, we can use AMSA to reflect the state of myocardial energy metabolism indirectly. Figure The changes of AMSA and relationship between AMSA and glycogen content:(A) The change of AMSA between VF/CRP group and VF group;(B) The relationship between AMSA and glycogen content. AMSA, amplitude spectrum area; V, time of ventricular fibrillation; # p &lt;0.05 vs. V4.

Exercise training has restorative potential on myocardial energy metabolism in rats with chronic heart failure.

Objective(s):Exercise training is a well-known accelerator for the treatment of chronic heart failure (CHF). The current study aimed to investigate the restorative effects of aerobic interval training (AIT) intervention on myocardial energy metabolism in CHF rats. Materials and Methods: Post-myocardial infarction (MI) heart failure animal model was established. The Sprague-Dawley rats were randomly divided into sham operation group (Sham group), CHF model group, and CHF exercise group (Exercise-CHF group). Results:Our data showed that when compared to the Sham group, the left ventricular systolic pressure (LVSP), myocardial glycogen content, and expression levels of key components of AMP-activated protein kinase (AMPK) pathway were decreased significantly (P<0.05) in the CHF-model group, while the left ventricular end diastolic pressure (LVEDP), fatty acid (FA) concentration, lactic acid content, and AMPKα phosphorylation (p-AMPKα) were increased significantly (P<0.05) in the CHF-model group. Importantly, AIT reversed these alterations induced by post-MI. Conclusion:Findings of this study demonstrated that AIT could improve the metabolic remodeling and enhance cardiac function, which may be associated with the activation of AMPK/ peroxisome proliferator activated receptor α (PPARα) and its downstream signaling pathway.

Diabetes-induced diastolic dysfunction is associated with myocardial glycogen accumulation and disrupted autophagy signalling

Diabetes-induced diastolic dysfunction is associated with myocardial glycogen accumulation and disrupted autophagy signalling

The peripheral chemoreflex: indefatigable guardian of fetal physiological adaptation to labour

The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic-ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5-2min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour.

Mechanism underlying inhibition of inflammatory responses induced by α7nAChR agonist postconditioning alone or in combination with remote limb ischemic postconditioning during myocardial I/R in rats: the relationship with GSK-3β

Objective To evaluate the relationship between the mechanism underlying inhibition of inflammatory responses induced by α7 nicotinic acetylcholine receptor(α7nAChR)agonist postconditioning alone or in combination with remote limb ischemic postconditioning during myocardial ischemia-reperfusion(I/R)and glycogen synthase kinase-3β(GSK-3β)in rats. Methods Eighty adult male Sprague-Dawley rats, aged 8 weeks, weighing 290-320 g, were divided into 4 groups(n=20 each)using a random number table: I/R group, α7nAChR agonist postconditioning group(group P), remote limb ischemic postconditioning group(group L)and α7nAChR agonist postconditioning plus remote limb ischemic postconditioning group(group P+ L). Myocardial I/R was induced by 30 min occlusion of the left anterior descending branch of coronary artery followed by 120 min reperfusion.Specific α7nAChR agonist PNU282987 2 mg/kg was intravenously injected immediately before reperfusion in group P. In group L, limb ischemia was induced by tourniquet occlusion of bilateral hind paws for 10 min starting from 20 min of myocardial ischemia, and the tourniquet was released at the beginning of reperfusion.Combination of intervention measures previously described in P and L groups was performed in group P+ L.Venous blood samples were taken at 120 min of reperfusion for determination of serum troponin I(TnI)and creatine kinase-MB(CK-MB)concentrations, myocardial infarct size(IS)and expression of phosphorylated GSK-3β [p-GSK-3β(Ser536)], NF-κBp65 and phosphorylated nuclear factor-κBp65(p-NF-κBp65)in myocardial tissues(by Western blot). Results Compared with group I/R, myocardial IS and serum cTnI and CK-MB concentrations were significantly decreased, the expression of p-GSK-3β(Ser9)in ischemic area was up-regulated, and the expression of p-NF-κBp65 in ischemic area was down-regulated in P, L and P+ L groups(P<0.05). Compared with group L, myocardial IS and serum cTnI and CK-MB concentrations were significantly decreased, the expression of p-GSK-3β(Ser9)in ischemic area was up-regulated, and the expression of p-NF-κBp65 in ischemic area was down-regulated in group P+ L(P<0.05). Conclusion The mechanism by which α7nAChR agonist postconditioning alone or in combination with remote limb ischemic postconditioning inhibits inflammatory responses during myocardial I/R may be related to inhibiting GSK-3β activity in rats. Key words: Myocardial reperfusion injury; Inflammation; Glycogen synthase kinase 3; Cholinergic agonists; Extremities; Ischemic postconditioning

Human γ2-AMPK Mutations.

In humans, dominant mutations in the gene encoding the regulatory γ2-subunit of AMP-activated protein kinase (PRKAG2) result in a highly penetrant phenotype dominated by cardiac features: left ventricular hypertrophy, ventricular pre-excitation, atrial tachyarrhythmia, cardiac conduction disease, and myocardial glycogen storage. The discovery of a link between the cell's fundamental energy sensor, AMPK, and inherited cardiac disease catalyzed intense interest into the biological role of AMPK in the heart. In this chapter, we provide an introduction to the spectrum of human disease resulting from pathogenic variants in PRKAG2, outlining its discovery, clinical genetics, and current perspectives on its pathogenesis and highlighting mechanistic insights derived through the evaluation of disease models. We also present a clinical perspective on the major components of the cardiomyopathy associated with mutations in PRKAG2, together with less commonly described extracardiac features, its prognosis, and principles of management.

Role of insulin receptors in myocardial ischaemia-reperfusion injury during cardiopulmonary bypass.

Ischaemia-reperfusion injury after cardiac bypass causes cardiac dysfunction and tissue damage. Insulin resistance during reperfusion contributes to the dysfunction, but the role of changes in myocardial insulin receptors during this period has not been determined yet. Twelve mongrel dogs underwent cardiac bypass, 6 for 30 min and 6 for 120 min. Blood samples were taken from the coronary artery and coronary sinus and tissue samples from the apex of the left ventricle before bypass and 15, 45, and 75 min after termination of bypass surgery and initiation of reperfusion. Plasma glucose and insulin, the Insulin Resistance Index, myocardial glycogen, insulin receptor alpha and beta subunits, and total insulin mRNA were measured in these samples. Plasma glucose and insulin and the insulin resistance index all increased significantly during the reperfusion period. A significant decrease in myocardial glycogen occurred at the same time. The alpha subunits of the insulin receptor were seen on the myocyte surface and the beta subunits mostly in the cytoplasm.The expression of both subunits and total insulin mRNA decreased in a similar manner after termination of bypass surgery. All parameters gradually returned toward pre-bypass values as the post-bypass period progressed. And at all post-bypass time points, the 120-min bypass group showed a significantly greater effect from ischaemia than the 30-min bypass group. A decrease in insulin receptor expression is a cause of post-bypass insulin resistance, and this decrease is initiated at the mRNA level. Increased insulin resistance leads to excessive reliance on myocardial glycogen as an energy source and a deficit in energy substrates that contributes to cardiac dysfunction.

Yakton and mexicor influence on the indicators of glycolysis, glyconeogenesis and energoproduct function of mitochondria in the rats’ myocardium in the conditions of doxorubicin cardiomyopathy

Doxorubicin – basic drug for the neoplastic diseases treatment, it’s main adverse effect is cardiotoxicity. The development of this complication is connected with the energy metabolism, prooxidant-antioxidant homeostasis, disturbances and influence on the genetic apparatus.The aim of the study – to state the succin acid’ derivatives – yakton and mexicor influence on indicators of glycolysis, glyconeogenesis and energoproduct function of mitochondria in the rats’ myocardium in the conditions of doxorubicin cardiomyopathy.Results. In was found that myocardial pyruvate, malate, isocitrate, glycogen, glucose-6-phosphate level and malatdegidrogenase activity were decreased in rats with doxorubicin cardiomyopathy. In comparison lactate lactate level increased.Conclusion. Succin acid’ derivatives – yakton and mexicor, administering with doxorubicin, protect glycolysis, glyconeogenesis and energoproduct function of mitochondria in the rats’ myocardium.

Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose

Disturbed systemic glycemic and insulinemic status elicits cardiomyocyte metabolic stress and altered glucose handling. In diabetes, pathological myocardial glycogen accumulation occurs. Recently, evidence of a specific myocardial autophagic degradation pathway for glycogen ("glycophagy") has been reported, differentiated from the more well-characterized protein "macrophagy" pathway. The goal of this study was to identify potential mechanisms involved in cardiac glycogen accumulation, glycophagy, and macrophagy regulation using cultured neonatal rat ventricular myocytes (NRVMs). In NRVMs, insulin-induced Akt phosphorylation was evident with 5 mM-glucose conditions (∼2.3-fold increased). Under high-glucose (30 mM) conditions, insulin-augmented phosphorylation was not observed. Accumulation of glycogen was observed in response to insulin only in high-glucose conditions (∼2-fold increase). Increased expression of the glycophagy marker starch-binding domain-containing protein-1 (STBD1, 25% increase) was observed under high-glucose and insulin conditions. Expression levels of the macrophagy markers p62 and light chain protein 3BII:I were not increased by insulin at either glucose level. Preliminary results from hearts of streptozotocin-treated diabetic rats are supportive of the findings obtained in NRVMs, suggesting diabetes induced elevated expression of STBD1 and of an additional glycophagy marker GABA(A) receptor-associated protein-like 1. Confocal microscopy demonstrated that light chain protein 3B and STBD1 immunomarkers were not colocalized in NRVMs. These findings provide the first evidence that cardiomyocyte glycophagy induction occurs under the influence of insulin and is responsive to extracellular high glucose. This study suggests that the regulation of glycogen content and glycophagy induction in the cardiomyocyte may be linked, and it is speculated that glycogen pathology in diabetic cardiomyopathy has glycophagic involvement.

Effects of GPIIb/IIIa-Inhibitor on Myocardial Glycogen Content and Edema Formation in Ischemic Pig Hearts in the Setting of Deep Hypothermic Circulatory Arrest

Effects of GPIIb/IIIa-Inhibitor on Myocardial Glycogen Content and Edema Formation in Ischemic Pig Hearts in the Setting of Deep Hypothermic Circulatory Arrest

Does resveratrol improve insulin signaling in chronically ischemic myocardium?

BackgroundResveratrol is a naturally occurring polyphenol believed to be cardioprotective. We previously demonstrated that resveratrol improves insulin signaling and glucose metabolism in liver and skeletal muscle of swine with metabolic syndrome. Although resveratrol has metabolic benefits in peripheral tissues, its effect on insulin signaling in ischemic myocardium (IM) is unclear. Therefore, we developed a clinically relevant swine model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of resveratrol on insulin signaling in cardiac tissue. Materials and methodsThirteen male Yorkshire swine were fed a high-cholesterol diet for 4 wk then underwent surgical placement of an ameroid constrictor to their circumflex artery to induce chronic myocardial ischemia. The high-cholesterol control group was given no drug (n = 7). The experimental group was provided the same diet and received supplemental resveratrol (100 mg/kg/d) (n = 6). Tissue was harvested 7 wk after ameroid placement for western blot and histological analyses. ResultsIn IM, there was no significant difference between the two groups in the insulin signaling markers studied. In nonischemic myocardium, there was a significant decrease in phosphorylated AMP-activated protein kinase α (P = 0.021) in the group treated with resveratrol; otherwise, there were no significant differences between the groups. Immunostaining for glucose transporter 4 and Periodic acid-Schiff staining for myocardial glycogen stores was similar between the groups. ConclusionsResveratrol has complex effects on glucose metabolism. Although prior studies demonstrated that resveratrol supplementation improves insulin sensitivity in peripheral tissues, in chronically IM, there are no significant alterations.

High-fat, low-carbohydrate diet alters myocardial oxidative stress and impairs recovery of cardiac function after ischemia and reperfusion in obese rats

Obesity is associated with elevated risk of heart disease. A solid understanding of the safety and potential adverse effects of high-fat, low-carbohydrate diet (HFLCD) similar to that used by humans for weight loss on the heart is crucial. High fat intake is known to promote increases in reactive oxygen species and mitochondrial damage. We hypothesized that there would be adverse effects of HFLCD on myocardial ischemia/reperfusion injury through enhancing oxidative stress injury and impairing mitochondrial biogenesis in a nongenetic, diet-induced rat model of obesity. To test the hypothesis, 250-g male Sprague-Dawley rats were fed an obesity-promoting diet for 7 weeks to induce obesity, then switched to HFLCD or a low-fat control diet for 2 weeks. Isolated hearts underwent global low flow ischemia for 60 minutes and reperfusion for 60 minutes. High-fat, low-carbohydrate diet resulted in greater weight gain and lower myocardial glycogen, plasma adiponectin, and insulin. Myocardial antioxidant gene transcript and protein expression of superoxide dismutase and catalase were reduced in HFLCD, along with increased oxidative gene NADPH oxidase-4 transcript and xanthine oxidase activity, and a 37% increase in nitrated protein (nitrotyrosine) in HFLCD hearts. The cardiac expression of key mitochondrial regulatory factors such as nuclear respiratory factor-1 and transcription factor A–mitochondrial were inhibited and myocardial mitochondrial DNA copy number decreased. The cardiac expression of adiponectin and its receptors was down-regulated in HFLCD. High-fat, low-carbohydrate diet impaired recovery of left ventricular rate-pressure product after ischemia/reperfusion and led to 3.5-fold increased injury as measured by lactate dehydrogenase release. In conclusion, HFLCD leads to increased ischemic myocardial injury and impaired recovery of function after reperfusion and was associated with attenuation of mitochondrial biogenesis and enhanced oxidative stress in obese rats. These findings may have important implications for diet selection in obese patients with ischemic heart disease.