Abstract 12780: Reduced Skeletal Muscle Lipid Uptake Affects Cardiac Substrate Metabolism and Leads to Cardiomyopathy
Skeletal muscle lipid content correlates with insulin action, however, effects of alterations of lipid metabolism in skeletal muscle on cardiac function have not been shown. Lipoprotein lipase (LPL) is important to lipid delivery in skeletal muscle and muscle enzyme activity increases with exercise and is markedly reduced with inactivity. We have created mice deficient in skeletal muscle LPL, which leads to altered lipid partitioning. By 3 mo insulin-mediated glucose uptake was reduced by 50% in the heart (p=0.006), despite maintenance of normal whole body insulin sensitivity and increased insulin sensitivity in skeletal muscle. Myocardial TG content was unchanged, but there were striking increases in PPAR-α gene expression (50%, p=0.001) and downstream signaling pathways i.e. 4-fold in carnitine palmitoyltransferase 1b (Cpt1b) (p<0.001); 1.5-fold in malonyl-CoA decarboxylase (MCD) (p≤0.001); 1.9-fold in acyl-CoA palmitoyl oxidase 1 (Acox1) (p=0.005); and 1.7-fold in acetyl-CoA carboxylase 2 (ACC2) (p=0.002). In addition, a 2.9 fold increase in CD36 (p<0.001) indicated a potential mechanism for the increased lipid uptake by the heart. Moreover, a 2.9 fold increase in PGC-1α (p<0.001) and 3.3 fold increase in pyruvate dehydrogenase kinase 4 (PDK4) mRNAs (p<0.001) suggested a shift in mitochondrial oxidation from carbohydrate to lipid. At 8 mo, myocardial PPARα, MCD, and CD36 gene expression was similar to that of control mice, and the other increases in gene expression were much less than at 3 mo, indicating a decreased capacity to increase fatty acid oxidation with age. By 12 mo, substantial impairments in cardiac size and function were observed, i.e. cardiac mass was increased by 50% and left ventricular diameter by 30%, whereas fractional shortening was decreased by 40%. Together, these results indicate that deletion of LPL in skeletal muscle alters lipid partitioning not just to skeletal muscle but to other peripheral tissues, and induces insulin resistance and increases in PPAR-α dependent gene expression in the myocardium. Thus, our data demonstrate that alterations in skeletal muscle metabolism similar to those with “inactivity” lead to marked secondary changes in cardiac substrate metabolism and cardiomyopathy.
- © 2010 by American Heart Association, Inc.