INCREASED CARNITINE PALMITOYLTRANSFERASE IN CARDIAC MYOCYTES IS MEDIATED BY INSULIN GROWTH-FACTOR-I

The mitochondrial carnitine palmitoyltransferase (CPT) system is compo sed of two proteins, CPT-I and -II, which, together with carnitine acy lcarnitine translocase, are involved in the transport of fatty acids i nto the mitochondrial matrix for beta-oxidation. In the liver, CPT-I a nd its inhibition by malonyl-CoA are sensitive to hormonal (10(-9) M) levels of insulin; however, a similar effect of insulin on heart CPT i s controversial. In cultured neonatal rat cardiac myocytes, tissue cul ture concentrations (1.7 mu M) of insulin increase CPT and cytochrome oxidase activities as well as mitochondrial protein synthesis, suggest ing that a growth mechanism may be involved. Because insulin at high c oncentrations may interact with the insulinlike growth factor (IGF-I) receptor, the consequences of insulin's action on heart cells in cultu re may be mediated through the IGF pathway. Consistent with an IGF-med iated pathway for the effect of insulin, incorporation of radioactivit y into immunoprecipitated CPT-II from insulin-treated cardiac myocytes is dramatically increased over control cells. The amount of immunorea ctive CPT-I is also increased in insulin-treated cells. Moreover, an I GF-I analogue that inhibits the autophosphorylation of the IGF-I recep tor blunts the insulin-mediated increase in CPT-I and -II activities b y >70%. At low physiologically relevant concentrations (10 ng/ml), IGF -I significantly increases the activities of both CPT-I and -II, and t he IGF-I analogue eliminates the IGF-I response. This is the first stu dy to suggest involvement of the IGF-I pathway in the regulation of mi tochondrial CPT synthesis and activities in the heart.