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

Abstract

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 age-dependent 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.