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Low exercise tolerance has a large influence on health status in chronic obstructive pulmonary disease and chronic heart failure. In addition to primary organ dysfunction, impaired skeletal muscle performance is a strong predictor of low exercise capacity. There are striking similarities between both disorders with respect to the muscular alterations underlying the impairment. However, different alterations occur in different muscle types. Histologic and metabolic data show that peripheral muscles undergo a shift from oxidative to glycolytic energy metabolism, whereas the opposite is observed in the diaphragm. These findings are in line with the notion that peripheral and diaphragm muscle are limited mainly by endurance and strength capacity, respectively. In both diseases, muscular impairment is multifactorially determined; hypoxia, oxidative stress, disuse, medication, nutritional depletion, and systemic inflammation may contribute to the observed muscle abnormalities and each factor has its own potential for innovative treatment approaches.

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In the eukaryotic cell an intrinsic mechanism is present providing the ability to defend itself against external stressors from various sources. This defense mechanism probably evolved from the presence of a group of chaperones, playing a crucial role in governing proper protein assembly, folding, and transport. Upregulation of the synthesis of a number of these proteins upon environmental stress establishes a unique defense system to maintain cellular protein homeostasis and to ensure survival of the cell. In the cardiovascular system this enhanced protein synthesis leads to a transient but powerful increase in tolerance to such endangering situations as ischemia, hypoxia, oxidative injury, and endotoxemia. These so-called heat shock proteins interfere with several physiological processes within several cell organelles and, for proper functioning, are translocated to different compartments following stress-induced synthesis. In this review we describe the physiological role of heat shock proteins and discuss their protective potential against various stress agents in the cardiovascular system.

Contraction of rat cardiac myocytes induces translocation of fatty acid translocase (FAT)/CD36 and GLUT4 from intracellular stores to the sarcolemma, leading to enhanced rates of long-chain fatty acid (FA) and glucose uptake, respectively. Because intracellular AMP/ ATP is elevated in contracting cardiac myocytes, we investigated whether activation of AMP-activated protein kinase (AMP kinase) is involved in contractioninducible FAT/CD36 translocation. The cell-permeable adenosine analog 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) and the mitochondrial inhibitor oligomycin, similar to 4-Hz electrostimulation, evoked a more than threefold activation of cardiomyocytic AMP kinase. Both AICAR and oligomycin stimulated FA uptake into noncontracting myocytes by 1.4-and 2.0-fold, respectively, but were ineffective in 4 Hz-contracting myocytes. These findings indicate that both agents stimulate FA uptake by a similar mechanism as electrostimulation, involving activation of AMP kinase, as evidenced from phosphorylation of acetyl-CoA carboxylase. Furthermore, the stimulating effects of both AICAR and oligomycin were antagonized by blocking FAT/CD36 with sulfo-N-succinimidylpalmitate, but not by inhibiting phosphatidylinositol 3-kinase with wortmannin, indicating the involvement of FAT/CD36, but excluding a role for insulin signaling. Subcellular fractionation showed that oligomycin was able to mobilize intracellularly stored FAT/CD36 to the sarcolemma. We conclude that AMP kinase regulates cardiac FA use through mobilization of FAT/CD36 from a contractioninducible intracellular storage compartment. Diabetes 52:1627-1634, 2003 F atty acid translocase (FAT)/CD36 is increasingly becoming recognized as a physiologically important long-chain fatty acid (FA) transport facilitator within the sarcolemma of muscle tissues (1-3). We have gathered convincing evidence that FAT/ CD36-mediated FA uptake is a rate-limiting step in FA use by heart and skeletal muscle (2). Moreover, FA uptake appears to be regulated by translocation of FAT/CD36 from intracellular, presumably endosomal, stores to the sarcolemma. Insulin and cellular contractions are two important physiological factors able to recruit FAT/CD36 to the sarcolemma (4 -7). Interestingly, the stimulation of FA uptake by contractions was additive to that of insulin, indicating that both factors operate through independent mechanisms. Furthermore, wortmannin completely blocked insulin-inducible FA uptake but had no effect on contraction-inducible FA uptake. Altogether, these findings indicate that insulin-inducible and contraction-inducible FAT/ CD36 pools are stored in two distinct intracellular sites (7). Strikingly, the effects of insulin and contractions on FA uptake by translocation of FAT/CD36 are remarkably similar to their effects on glucose uptake by translocation of the glucose transporter GLUT4 from insulin-inducible and contraction-inducible intracellular stores (7). Whereas the wortmannin sensitivity of insulin-inducible FA uptake indicates an involveme...

Abstract-Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPAR␣ in FA-mediated expression has been demonstrated, the role of the PPAR␤/␦ and PPAR␥ isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPAR␣ (Wy-14,643), PPAR␤/␦ (L-165041, GW501516), or PPAR␥ (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPAR␣ and PPAR␤/␦ ligands, but not to PPAR␥ ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPAR␣ and PPAR␤/␦, but not by PPAR␥ ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPAR␤/␦, the FA-induced expression of genes was mimicked by the PPAR␤/␦ ligand only, indicating that FA also act as ligands for the PPAR␤/␦ isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPAR␥ ligands. However, addition of PPAR␣ and PPAR␤/␦ ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPAR␣, PPAR␤/␦, but not PPAR␥, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPAR␤/␦ in cardiac disease.

Fatty acids play critical roles in mammalian energy metabolism. Moreover, they are important substrates for the synthesis of membrane phospholipids and biologically active compounds like eicosanoids and leukotrienes. Because of their low solubility in aqueous solutions such as blood plasma and interstitial fluid, fatty acids are in need of binding proteins to increase their concentration in vascular and interstitial compartments. Albumin acts as main fatty acid binding protein in extracellular fluids. Plasma albumin possesses about 7 binding sites for fatty acids with moderate to high affinity, enhancing the concentration of fatty acids by a several orders of magnitude. Despite the high affinity of albumin for fatty acids, uptake of fatty acids by parenchymal cells such as skeletal and cardiac myocytes seems not to be hampered by albumin. In contrast, experimental findings suggest that albumin may facilitate the uptake of fatty acids by organs in need of these substrates. In the present overview the following issues will be briefly discussed: (i) transport and storage of fatty acids in the mammalian body, (ii) biosynthesis of albumin in the liver, (iii) localization and concentration of albumin in body fluids, (iv) interactions between albumin and fatty acids, (v) albumin structure and fatty acid binding sites, (vi) uptake of fatty acids by organs and roles for plasma albumin and (vii) lessons from patients and experimental animals lacking plasma albumin.

We performed studies 1) to investigate the kinetics of palmitate transport into giant sarcolemmal vesicles, 2) to determine whether the transport capacity is greater in red muscles than in white muscles, and 3) to determine whether putative long-chain fatty acid (LCFA) transporters are more abundant in red than in white muscles. For these studies we used giant sarcolemmal vesicles, which contained cytoplasmic fatty acid binding protein (FABPc), an intravesicular fatty acid sink. Intravesicular FABPcconcentrations were sufficiently high so as not to limit the uptake of palmitate under conditions of maximal palmitate uptake (i.e., 4.5-fold excess in white and 31.3-fold excess in red muscle vesicles). All of the palmitate taken up was recovered as unesterified palmitate. Palmitate uptake was reduced by phloretin (−50%), sulfo- N-succinimidyl oleate (−43%), anti-plasma membrane-bound FABP (FABPpm, −30%), trypsin (−45%), and when incubation temperature was lowered to 0°C (−70%). Palmitate uptake was also reduced by excess oleate (−65%), but not by excess octanoate or by glucose. Kinetic studies showed that maximal transport was 1.8-fold greater in red vesicles than in white vesicles. The Michaelis-Menten constant in both types of vesicles was ∼6 nM. Fatty acid transport protein mRNA and fatty acid translocase (FAT) mRNA were about fivefold greater in red muscles than in white muscles. FAT/CD36 and FABPpm proteins in red vesicles or in homogenates were greater than in white vesicles or homogenates ( P < 0.05). These studies provide the first evidence of a protein-mediated LCFA transport system in skeletal muscle. In this tissue, palmitate transport rates are greater in red than in white muscles because more LCFA transporters are available.