No abstract

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.

No abstract

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...