Contribution of Glycogen to Aerobic Myocardial Glucose Utilization

Henning, Sarah L.; Wambolt, Richard B.; Schönekess, Brett O.; Lopaschuk, Gary D.; Allard, Michael F.

doi:10.1161/01.cir.93.8.1549

Cited by 106 publications

(90 citation statements)

References 21 publications

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“…Increases in both myocardial intracellular and extracellular lipids and decreases in myocardial glycogen stores in senescent mice suggest that the transformation rate from lipid to glycogen utilization occurs with aging, so that glycogen storage in the myocardium is insufficient. In the young healthy myocardium, glycogen is preferentially oxidized over exogenous glucose and undergoes significant turnover (Goodwin et al 1995;Goodwin et al 1996;Henning et al 1996). Our results suggest that the decrease of glycogen storage may contribute to LV dysfunction in senescent mice.…”

Section: Discussionmentioning

confidence: 70%

Age-related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms

Lin

Lopez

Jin³

et al. 2008

Experimental Gerontology

100

109

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Age-related skeletal muscle sarcopenia has been extensively studied and smooth muscle sarcopenia has been recently described, but age-related cardiac sarcopenia has not been previously examined. Therefore, we evaluated adult (7.5±0.5 months; n=27) and senescent (31.8±0.4 months; n=26) C57BL/6J mice for cardiac sarcopenia using physiological, histological, and biochemical assessments. Mice do not develop hypertension, even into senescence, which allowed us to decouple vascular effects and monitor cardiac-dependent variables. We then developed a mathematical model to describe the relationship between age-related changes in cardiac muscle structure and function. Our results showed that, compared to adult mice, senescent mice demonstrated increased left ventricular (LV) end diastolic dimension, decreased wall thickness, and decreased ejection fraction, indicating dilation and reduced contractile performance. Myocyte numbers decreased, and interstitial fibrosis was punctate but doubled in the senescent mice, indicating reparative fibrosis. Electrocardiogram analysis showed that PR interval and QRS interval increased and R amplitude decreased in the senescent mice, indicating prolonged conduction times consistent with increased fibrosis. Intracellular lipid accumulation was accompanied by a decrease in glycogen stores in the senescent mice. Mathematical simulation indicated that changes in LV dimension, collagen deposition, wall stress, and wall stiffness precede LV dysfunction. We conclude that age-related cardiac sarcopenia occurs in mice and that LV remodeling due to increased end diastolic pressure could be an underlying mechanism for age-related LV dysfunction.

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Section: Discussionmentioning

confidence: 70%

Age-related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms

Lin

Lopez

Jin³

et al. 2008

Experimental Gerontology

100

109

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“…Glycogen accumulation and the preferential oxidation of glucose liberated from glycogen may provide an energetic advantage, and it also lessens the potential for glycolysis and proton production (13,29). Glycogen synthesis is an important target in cyclohexyladenosine-induced cardioprotection (7), but whether the ability of p38 MAPK inhibitors to relieve the adenosine-induced suppression of glycogen synthesis in stressed hearts translates into enhanced cardioprotection following severe ischemia remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

Jaswal¹,

Gandhi²,

Finegan³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Clanachan AS. p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5Ј-AMP-activated protein kinase. Am J Physiol Heart Circ Physiol 292: H1978 -H1985, 2007. First published December 15, 2006; doi:10.1152/ajpheart.01121.2006.-Adenosineinduced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5Ј-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 ϫ 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.adenosine; adenosine 5Ј-monophosphate-activated protein kinase; glycogen metabolism CARDIOPROTECTION INDUCED BY adenosine and the adenosine A 1 receptor agonist N 6 -cyclohexyladenosine may be related to their ability to stimulate glycogen synthesis and inhibit glycolysis and proton production during reperfusion following ischemia (7, 9). However, our laboratory has shown that in hearts stressed by transient ischemia, there is a loss of adenosineinduced cardioprotection (8), an effect consistent with the lower cardioprotective effectiveness of adenosine and adenosine mimetic agents in studies involving patients with coronary artery disease (24). Because this model of transient ischemia differs from ischemic preconditioning, in that the transient ischemia does not enhance the recovery of left ventricular (LV) function following severe ischemia (8), stressing by transient ischemia may provide a unique system in which to study the mechanisms underlying the loss of adenosine-induced cardioprotection observe...

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“…33 Glycogen breakdown is also rapidly stimulated during sudden increases of heart work. 34,35 Glucosyl moieties coming from glycogen breakdown are preferentially oxidized rather than converted to lactate. 34 As a result, there is a dichotomy between glucosyl units coming from extracellular glucose, which are metabolized into lactate, and glucosyl units coming from glycogen, which are oxidized.…”

Section: Glycogen Metabolismmentioning

confidence: 99%