Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

Jessen, Michael E.; Kovarik, T E; Jeffrey, F. M H; Sherry, A. Dean; Storey, Charles; Chao, Robert; Ring, W. Steves; Malloy, Craig R.

doi:10.1172/jci116657

Cited by 33 publications

(14 citation statements)

References 42 publications

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“…It has been speculated that anaplerotic flux may serve as a biosensor between the cytoplasm and the mitochondria (11,36,39,43,48). Furthermore, evidence suggests a role for anaplerosis in the regulation of contractile function in the heart (15,23,30,42,49). Recent studies have also shown that flux through pyruvate carboxylase regulates amino acid synthesis (33,34) and may be important in controlling cell growth (34,43).…”

Section: Discussionmentioning

confidence: 99%

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

Hall

Gibbons

Chatham

2002

American Journal of Physiology-Endocrinology and Metabolism

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13C-nuclear magnetic resonance (NMR) spectroscopy was used to test our hypothesis that insulin-like growth factor I (IGF-I) stimulates glucose flux into both nonoxidative and oxidative pathways in vascular smooth muscle cells (VSMC). Rat VSMC were exposed to uniformly labeled [13C]glucose ([U-13C]glucose; 5.5 mM) and [3-13C]pyruvate (1 mM) in the presence and absence of IGF-I (100 ng/ml). IGF-I increased glucose flux through glycolysis and the tricarboxylic acid (TCA) cycle as well as total anaplerotic flux into the TCA cycle. Previous work in our laboratory identified an increase in GLUT1 content and glucose metabolism in neointimal VSMC that was sufficient to promote proliferation and inhibit apoptosis. To test whether IGF-I could potentiate the GLUT1-induced increased flux in the neointima, we utilized VSMC harboring constitutive overexpression of GLUT1. Indeed, IGF-I markedly potentiated the GLUT1-induced increase in glucose flux through glycolysis and the TCA cycle. Taken together, these findings demonstrate that upregulation of glucose transport through either IGF-I or increased GLUT1 content stimulates glucose flux through both nonoxidative and oxidative pathways in VSMC.

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Section: Discussionmentioning

confidence: 99%

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

Hall

Gibbons

Chatham

2002

American Journal of Physiology-Endocrinology and Metabolism

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“…Evidence of net anaplerosis from glutamine/glutamate would require the demonstration of simultaneous cataplerosis evidenced by (i) stimulation of gluconeogenesis in liver and kidney, or (ii) release of CAC intermediates and aspartate from non-gluconeogenic tissues. The effect of anaplerosis from glutamine/glutamate on cardiac function has been controversial, with positive and negative reports of improvement of cardiac function in animal models (Jessen et al 1993;Khogali et al 1998).…”

Section: Glutamine/glutamatementioning

confidence: 99%

Anaplerotic molecules: Current and future

Brunengraber

Roe

2005

J of Inher Metab Disea

177

168

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This review presents the concepts of anaplerosis and cataplerosis in relation to the regulation of citric acid cycle operation. Anaplerosis is the re-filling of the catalytic intermediates of the cycle that carry acetyl-CoA as it is oxidized. The main anaplerotic substrates are pyruvate, glutamine/glutamate and precursors of propionyl-CoA (odd-chain fatty acids, specific amino acids, C(5)-ketone bodies). Cataplerosis balances anaplerosis by removing excess intermediates from the citric acid cycle. The properties of the main anaplerotic substrates are reviewed from the point of view of potential clinical applications to the treatment of some inherited and acquired conditions.

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“…4). While the crucial role of anaplerosis for hepatic gluconeogenesis is self-evident, investigations in the heart suggested that stimulating anaplerosis from exogenous substrates could become part of the treatment of myocardial reperfusion injury and other cardiomyopathies (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver

Reszko

Kasumov

Pierce

et al. 2003

Journal of Biological Chemistry

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While a number of studies underline the importance of anaplerotic pathways for hepatic biosynthetic functions and cardiac contractile activity, much remains to be learned about the sites and regulation of anaplerosis in these tissues. As part of a study on the regulation of anaplerosis from propionyl-CoA precursors in rat livers and hearts, we investigated the degree of reversibility of the reactions of the propionyl-CoA pathway. Label was introduced into the pathway via NaH 13 CO 3 , [U- 13 Adequate energy production via the citric acid cycle (CAC) 1 requires not only a constant supply of acetyl-CoA, but also a fairly constant pool of the catalytic intermediates which carry the acetyl groups as they are oxidized. Although the process of anaplerosis in micro-organisms was discovered in the 1960s (1), its importance for the homeostasis of mammalian cells (particularly cardiomyocytes) was recognized only in the 1980s (2, 3) (for a recent review, see Ref. 4). While the crucial role of anaplerosis for hepatic gluconeogenesis is self-evident, investigations in the heart suggested that stimulating anaplerosis from exogenous substrates could become part of the treatment of myocardial reperfusion injury and other cardiomyopathies (5-10).In a recent clinical study (11), the hypoglycemia as well as the mechanical performance of the heart and muscle of patients suffering from long chain fatty acid oxidation defects was greatly improved by replacing the fat component of their therapeutic diet, i.e. trioctanoin (a medium-even-chain triglyceride) by triheptanoin (a medium-odd-chain triglyceride). The only difference between the metabolisms of octanoate and heptanoate is the production of propionyl-CoA from the latter. In a follow-up investigation in pig hearts, propionate infusion was found to be a very effective anaplerotic substrate. Anaplerosis from 0.25 mM [U-13 C 3 ]propionate amounted to 9% of the rate of the CAC (12, 13). This led us to investigate the regulation of the propionyl-CoA pathway in livers and hearts of animals.Propionyl-CoA is formed from the activation of propionate and from the catabolism of isoleucine, valine, threonine, methionine, cholesterol, odd-chain fatty acids, and C 5 -ketone bodies (14). In mammalian tissues, the metabolism of propionyl-CoA (Fig. 1) involves (i) the formation of (S)-methylmalonyl-CoA by biotin-dependent propionyl-CoA carboxylase (15), (ii) the conversion of (S)-to (R)-methylmalonyl-CoA by methylmalonyl-CoA racemase (16), and (iii) the isomerization of (R)-methylmalonyl-CoA to succinylCoA by cobalamine-dependent methylmalonyl-CoA mutase (17-19) (for a recent review, see Ref. 20).Early in vitro work with purified enzymes revealed different degrees of reversibility of the reactions catalyzed by propionylCoA carboxylase (21, 22), methylmalonyl-CoA racemase (23), and methylmalonyl-CoA mutase (24). In the presence of a mixture of purified propionyl-CoA carboxylase, methylmalonylCoA racemase, and methylmalonyl-CoA mutase, only a few percent of the radioactivity of [ 14 C]succinyl-CoA...

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Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart.

Cited by 33 publications

References 42 publications

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells

Anaplerotic molecules: Current and future

Assessing the Reversibility of the Anaplerotic Reactions of the Propionyl-CoA Pathway in Heart and Liver

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