Acid sphingomyelinase inhibitors, imipramine and zoledronic acid, increase skeletal muscle tissue sensitivity to insulin action at old age.

Malfunction of skeletal muscles and dysregulated turnover of sphingolipids in the insulin responsive tissues have been determined at old age. Present article investigates the role of acid sphingomyelinase (SMase)-dependent ceramide accumulation in reduction of the skeletal muscle sensitivity to insulin action at old age. The 3-, 12- and 24-month-old Wistar male rats were used in the experiments. The progressive increase of ceramide content and ceramide/sphingomyeline (SM) ratio was determined in the extensor digitorum longus (EDL) muscle during aging of rats. The agedependent ceramide accumulation was followed by reduction of muscle tissue response to insulin action. The resistance of EDL to insulin action at old age can be imitated by exogenous natural N-palmitoyl-D-erythro-sphingosine (C16-ceramide) injection to adult rats, while imipramine or zoledronic acid treatment of old animals nullified dysregulation of SM turnover and improved the muscle tissue response to insulin action. Drugs significantly increased insulin-stimulated 2-D-[3H] glucose uptake by the EDL muscle of 24-month-old animals to the level close to that of 3-month-old rats in both in vivo and in vitro experiments. Imipramine, as well as zoledronic acid significantly reduced acid SMase activity in the EDL of old animals. Thus, ceramide overproduction via acid SMase activation can be important for the development of EDL resistance to insulin action. Therefore, acid SMase inhibitors can possibly be used as therapeutic tools for improvement of muscle tissue sensitivity to insulin action at an old age.

Role of acid sphingomyelinase in the age-dependent dysregulation of sphingolipids turnover in the tissues of rats.

Old age-associated pathologies usually coincide with altered sphingolipid metabolism. In the present article, the role of acid sphingomyelinase (ASMase) in the age-dependent changes of sphingomyelin (SM) and ceramide contents in the tissues has been investigated by means of ASMase inhibitors, imipramine and zoledronic acid. It has been determined that ceramide content and ceramide/SM ratio increased, while SM level decreased in the heart, liver, blood serum and skeletal muscles of 24-month old rats in contrast to 3-month old animals. Injections of imipramine or zoledronic acid to 24-month old rats resulted in significant downregulation of ASMase in the liver and skeletal and heart muscles. The both inhibitors decreased the ceramide content and ceramide/SM ratio and increased the SM content in all tissues studied, except the heart, of old rats to the levels close to those observed in the young animals. Long-term treatment of rats by inhibitors, which have different mechanisms of action on ASMase, exerts the similar, but not equal effects on enzyme activity and SM turnover. In summary, the data above strongly suggest that the age-dependent up-regulation of ASMase plays an important role in the modulation of ceramide and SM contents in rat tissues and that imipramine and zoledronic acid are useful tools for SM turnover manipulation at old age.