THE LONG-TERM REGULATION OF SKELETAL-MUSCLE PYRUVATE-DEHYDROGENASE KINASE BY DIETARY-LIPID IS DEPENDENT ON FATTY-ACID COMPOSITION

The provision of a diet high in saturated and monounsaturated fat for 28 days evoked a significant (1.9-fold) increase in pyruvate-dehydrogenase kinase activity measured in isolated mitochondria from representative slow-twitch (oxidative) skeletal muscles (pooled soleus and adductor longus muscles) from adult rats. The increase observed in response to 28 days of high-fat feeding in slow-twitch skeletal muscle mitochondria was similar in magnitude to that observed in heart mitochondria. Pyruvate-dehydrogenase kinase activity was not increased in response to the provision of the high-fat diet in mitochondria prepared from a representative fast-twitch muscle (tibialis anterior), while the increases evoked by 28 days of high-fat feeding in cardiac and slow-twitch skeletal muscle were prevented by the replacement of 7% of the dietary fatty acids with long-chain omega-3 fatty acids from marine oil. Cardiac myocytes prepared from the high-fat-fed rats showed impaired responses of this enzyme to n-octanoate (1 mM) and N-6,2-O-dibutyryl-adenosine 3',5'-monophosphate (50 mu M) individually in cultured cardiac myocytes and of glucose uptake to insulin at low concentrations in freshly prepared cardiac myocytes, compared with control rats maintained on standard low-fat/high-carbohydrate diet. These impairments in responses to agonists were substantially improved by the inclusion of long-chain omega-3 fatty acids in the high-fat diet. The results indicate that pyruvate-dehydrogenase kinase activity in oxidative skeletal muscle is a target for longer-term regulation by high-fat feeding and that the fatty acid composition of the diet, rather than the fat content, is a key influence.