Changes in Cardiac Substrate Transporters and Metabolic Proteins Mirror the Metabolic Shift in Patients with Aortic Stenosis

In the hypertrophied human heart, fatty acid metabolism is decreased and glucose utilisation is increased. We hypothesized that the sarcolemmal and mitochondrial proteins involved in these key metabolic pathways would mirror these changes, providing a mechanism to account for the modified metabolic flux measured in the human heart. Echocardiography was performed to assess in vivo hypertrophy and aortic valve impairment in patients with aortic stenosis (n = 18). Cardiac biopsies were obtained during valve replacement surgery, and used for western blotting to measure metabolic protein levels. Protein levels of the predominant fatty acid transporter, fatty acid translocase (FAT/CD36) correlated negatively with levels of the glucose transporters, GLUT1 and GLUT4. The decrease in FAT/CD36 was accompanied by decreases in the fatty acid binding proteins, FABPpm and H-FABP, the β-oxidation protein medium chain acyl-coenzyme A dehydrogenase, the Krebs cycle protein α-ketoglutarate dehydrogenase and the oxidative phosphorylation protein ATP synthase. FAT/CD36 and complex I of the electron transport chain were downregulated, whereas the glucose transporter GLUT4 was upregulated with increasing left ventricular mass index, a measure of cardiac hypertrophy. In conclusion, coordinated downregulation of sequential steps involved in fatty acid and oxidative metabolism occur in the human heart, accompanied by upregulation of the glucose transporters. The profile of the substrate transporters and metabolic proteins mirror the metabolic shift from fatty acid to glucose utilisation that occurs in vivo in the human heart

Age-related morphological changes in skeletal muscle cells of acid alpha-glucosidase knockout mice

Glycogen storage disease type II (GSDII), caused by a genetic defect in acid -glucosidase (AGLU), leads to a decline in muscle contractility caused by both muscle wasting and a decrease in muscle quality, i.e., force generated per unit muscle mass. A previous study has shown that loss of muscle mass can only explain one-third of the decrease in contractile performance. Here we report on changes in the intramyocellular structural organization in a mouse knockout model (AGLU-/- mice) as a possible cause for the decline in muscle quality. Swollen, glycogen-filled lysosomes and centrally localized cores with cellular debris partially contribute to the decline in muscle quality. Altered localization and deposition of cytoskeletal proteins desmin and titin may reflect adaptive mechanisms at the age of 13 months, but a decline in quality at 20 months of age. The early deposition of lipofuscin in AGLU-deficient myocytes (13 months) is most likely a reflection of enhanced oxidative stress, which may also affect muscle quality. These collective findings, on the one hand, may explain the decrease in tissue quality and, on the other, may represent markers for efficacy of therapeutic interventions to restore muscle function in patients suffering from GSDI