Prevention of Skeletal Muscle Myopathy

Heart failure is a syndrome leading to a skeletal myopathy with muscle atrophy and shift toward fast contracting fibres. It has been shown that the major cause of atrophy is muscle waste due to skeletal muscle myonuclei apoptosis. Apoptosis is triggered by circulating cytokines and their second messengers, in particular sphingolipids. We report here several attempts to block apoptosis. Thalidomide, an inhibitor of TNFα biosynthesis, was used without success. More successful was the attempt with blocking the Angiotensin II receptors in that apoptosis and atrophy could be prevented. Another useful approach was the block of the apoptotic cascade involving sphyngomyelinase and caspases. This was done both in vivo and in vitro with a natural occurring substance: carnitine, that has been shown to be able to block both sphyngomyelinase and caspases. Aim of our previous studies was also to shed some light on the pathophysiology of the heart failure myopathy, but at the same time to see whether apoptosis could be inhibited with subsequent prevention of the myopathy (atrophy and MHCs shift) and improvement of exercise capacity and symptoms. Since these data suggest that it is possible to block the apoptotic cascade and prevent muscle waste and atrophy, the next step is to push research into heart failure in humans and maybe to other myopathies in which it has been shown that apoptosis plays a determinant role in producing myocyte loss.