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 N6,2-O-dibutyryladenosine 3',5'-monophosphate (50 microM) 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.