Thermoregulatory uncoupling in heart muscle mitochondria: involvement of the ATP/ADP antiporter and uncoupling protein

Simonyan, Ruben A.; Skulachev, Vladimir P.

doi:10.1016/s0014-5793(98)01106-5

Cited by 43 publications

(28 citation statements)

References 16 publications

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“…In addition, subsarcolemmal mitochondria were more sensitive than intermyofibrillar ones, whatever the diet, thus suggesting a specific role of subsarcolemmal mitochondria in the regulation of cellular energy coupling. It has been proposed that the uncoupling effect of fatty acids depends on the activity of mitochondrial carriers, such as the ATP=ADP antiporter, the dicarboxylate carrier, the aspartate=glutamate antiporter 33 and uncoupling proteins (UCP) 2 and 3. 34 Therefore, the higher sensitivity to palmitate of skeletal muscle mitochondrial populations from rats fed a high-fat diet could be due to an increase in the above mitochondrial carriers.…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle oxidative capacity in rats fed high-fat diet

et al. 2002

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OBJECTIVE: To investigate whether young rats respond to high-fat feeding through changes in energy efficiency and fuel partitioning at the level of skeletal muscle, to avoid obesity development. In addition, to establish whether the two mitochondrial subpopulations, which exist in skeletal muscle, ie subsarcolemmal and intermyofibrillar, are differently affected by high-fat feeding. DESIGN: Weaning rats were fed a low-fat or a high-fat diet for 15 days. MEASUREMENTS: Energy balance and lipid partitioning in the whole animal. State 3 and state 4 oxygen consumption rates in whole skeletal muscle homogenate. State 3 and state 4 oxygen consumption rates, membrane potential and uncoupling effect of palmitate in subsarcolemmal and intermyofibrillar mitochondria from skeletal muscle. RESULTS: Rats fed a high-fat diet showed an increased whole body lipid utilization. Skeletal muscle NAD-linked and lipid oxidative capacity significantly increased at the whole-tissue level, due to an increase in lipid oxidative capacity in subsarcolemmal and intermyofibrillar mitochondria and in NAD-linked activity only in intermyofibrillar ones. In addition, rats fed a highfat diet showed an increase in the uncoupling effect of palmitate in both the mitochondrial populations. CONCLUSIONS: In young rats fed a high-fat diet, skeletal muscle contributes to enhanced whole body lipid oxidation through an increased mitochondrial capacity to use lipids as metabolic fuels, associated with a decrease in energy coupling.

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Section: Discussionmentioning

confidence: 99%

Skeletal muscle oxidative capacity in rats fed high-fat diet

et al. 2002

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“…The latter effect, uncoupling, is thought to involve cyclic mitochondrial influx of fatty acid (R-COOH) and efflux of its anionic (R-COO Ϫ ) form (27,31). Translocation of the less membrane-permeant fatty acid anion across the inner membrane is rate limiting and has been deduced to be catalyzed by the ADP/ATP carrier and/or other inner mitochondrial membrane proteins such as uncoupling protein (5,17,30). The LC fatty acids probably flip-flop between the inner and outer face of the bilayer, delivering protons to the matrix (11), as schematically illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells

Ray

Noll

Daut

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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The effects of long-chain (LC) fatty acids on rate of heat production (heat rate) and mitochondrial membrane potential (⌬⌿) of intact guinea pig cardiac muscle were investigated at 37°C. Heat rate of ventricular trabeculae was measured with microcalorimetry, and ⌬⌿ was monitored in isolated ventricular myocytes with either JC-1 or tetramethylrhodamine ethyl ester (TMRE). Methyl-␤-cyclodextrin was used as fatty acid carrier. Application of 400 M oleate or linoleate increased resting heat rate by ϳ30% and ϳ25%, respectively. When LC fatty acid was supplied as sole metabolic substrate, resting heat rate was decreased by 3-mercaptopropionic acid. In TMRE-loaded myocytes, neither 40-80 M oleate nor 40 M linoleate affected ⌬⌿. At a higher concentration (400 M) both oleate and linoleate increased TMRE fluorescence by ϳ20% of maximum, obtained using 2,4-dinitrophenol (100 M), indicating a depolarization of the inner mitochondrial membrane. We conclude that LC fatty acids, at sufficiently high concentration, increase heat rate and decrease ⌬⌿ in intact cardiac muscle, consistent with a protonophoric uncoupling action. These effects may contribute to the high metabolic rate after reperfusion of postischemic myocardium. mitochondrial membrane potential; microcalorimetry IN CARDIAC MUSCLE, the resting (basal) level of metabolism is extraordinarily high, accounting for 25-30% of the metabolic rate of mechanically active muscle (3,4,9,12,22,29). Although the origin of this high resting metabolic rate is unknown, it has been shown to be sensitive to metabolic substrate (4, 9). This is well illustrated with pyruvate, which has been shown to increase resting rate of heat production (4) and oxygen consumption (9) of isolated cardiac muscle preparations.In isolated mitochondrial preparations, long-chain (LC) fatty acids have been shown convincingly to uncouple oxidative phosphorylation (27,31). Whether this uncoupling action manifests in intact cardiac muscle is not known (14,35). This unresolved issue is important because LC fatty acids are the major metabolic substrates of the heart and, furthermore, they are known to accumulate in high concentrations during ischemia (6, 33). The aims of the present study were to determine the effects of LC fatty acids on both resting heat rate and mitochondrial membrane potential (⌬⌿) of intact cardiac muscle. METHODS Isolation of trabeculae and microcalorimetry.Guinea pigs (200-300 g) were anesthetized with 3-4% isoflurane in oxygen and then decapitated with a guillotine. The heart was rapidly excised and perfused with dissecting solution containing (mM) 105 NaCl, 15 KCl, 2 CaCl 2, 1 MgCl2, 1 NaH2PO4, 24 NaHCO3, 20 2,3-butanedione monoxime, and 10 glucose. The solution was equilibrated with 95% O2-5% CO2, and the pH was 7.4. The right ventricle was opened, and free running trabeculae (diameter Ͻ400 m) were excised and subsequently transferred to the calorimeter. These preparations were shown recently to be composed chiefly of myocytes accompanied by parallel perimysial collagen fibers (13). Af...

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“…Moreover the fact that in isolated neonatal cardiomyocytes fatty acids were able to stimulate UCP2 gene expression to a significant extent, along with a panel of genes encoding proteins known to be involved in cardiac fatty acid transport and metabolism, strongly suggests a relationship between UCP2 and fatty acid handling. 50,16 An involvement of the uncoupling proteins has been hypothesized in the uncoupling effect of heart muscle mitochondria by high NEFA concentrations, 17,18 that could decrease the ATP formation and the heart work efficiency in the diabetic rat. 51 More recently, however, the putative uncoupling effect of these proteins has been questioned.…”

Section: Nefa and Gene Expression In Rat Heartmentioning

confidence: 99%

“…17,18 The newly discovered UCP2 is widely expressed in several tissues, and particularly in the normal rat heart muscle under basal conditions. 19 UCP3 is predominantly expressed in skeletal muscles and only slightly detectable in rat heart muscle.…”

Section: Introductionmentioning

confidence: 99%

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

et al. 2002

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OBJECTIVE: It has been reported that an increased availability of free fatty acids (NEFA) not only interferes with glucose utilization in insulin-dependent tissues, but may also result in an uncoupling effect of heart metabolism. We aimed therefore to investigate the effect of an increased availability of NEFA on gene expression of proteins involved in transmembrane fatty acid (FAT=CD36) and glucose (GLUT4) transport and of the uncoupling proteins UCP2 and 3 at the heart and skeletal muscle level. STUDY DESIGN: Euglycemic hyperinsulinemic clamp was performed after 24 h Intralipid 1 plus heparin or saline infusion in lean Zucker rats. Skeletal and heart muscle glucose utilization was calculated by 2-deoxy-[1-3 H]-D-glucose technique. Quantification of FAT=CD36, GLUT4, UCP2 and UCP3 mRNAs was obtained by Northern blot analysis or RT-PCR. RESULTS: In Intralipid 1 plus heparin infused animals a significant decrease in insulin-mediated glucose uptake was observed both in the heart (22.62 AE 2.04 vs 10.37 AE 2.33 ng=mg=min; P < 0.01) and in soleus muscle (13.46 AE 1.53 vs 6.84 AE 2.58 ng=mg=min; P < 0.05). FAT=CD36 mRNA was significantly increased in skeletal muscle tissue ( þ 117.4 AE 16.3%, P < 0.05), while no differences were found at the heart level in respect to saline infused rats. A clear decrease of GLUT4 mRNA was observed in both tissues. The 24 h infusion of fat emulsion resulted in a clear enhancement of UCP2 and UCP3 mRNA levels in the heart (99.5 AE 15.3 and 80 AE 4%) and in the skeletal muscle (291.5 AE 24.7 and 146.9 AE 12.7%). CONCLUSIONS: As a result of the increased availability of NEFA, FAT=CD36 gene expression increases in skeletal muscle, but not at the heart level. The augmented lipid fuel supply is responsible for the depression of insulin-mediated glucose transport and for the increase of UCP2 and 3 gene expression in both skeletal and heart muscle.

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Thermoregulatory uncoupling in heart muscle mitochondria: involvement of the ATP/ADP antiporter and uncoupling protein

Cited by 43 publications

References 16 publications

Skeletal muscle oxidative capacity in rats fed high-fat diet

Skeletal muscle oxidative capacity in rats fed high-fat diet

Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

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