Staurosporine Blocks the ATP-Sensitive K+Channels and Induces Atrophy in Rodent Skeletal Muscles

Abstract

The ATP-sensitive K+channels(KATP) has been proposed as a molecular sensor of atrophy in skeletal muscle(Tricarico et al., 2010). In the present work we evaluated the “in vitro” effects of staurosporine, a well known apoptotic agent, on sarcolemmal KATP channels and on muscle proteins content and fibers diameter in slow-twitch Soleus(SOL) and fast-twitch Exstensor Digitorum Longus(EDL) and Flexor Digitorum Brevis(FDB) muscles of mice. The isolated muscles and the single fibers were incubated with staurosporine (1 μg/mL) for 1-6-24-48 hrs. alone or in combination with diazoxide(100 μM-250 μM), a KATP opener, and the changes in the total proteins content, gene expression, fibers diameter and KATP channel activity were evaluated. We found that staurosporine blocks KATP channels in excised-patch experiments being more effective in SOL rather than in EDL and FDB fibers. The toxin also caused a reduction of the proteins content/muscle of −45%, −25% and −21% for SOL, EDL and FDB, respectively at 24 hrs. A time-dependent reduction of the diameter is observed following incubation of the fibers with staurosporine. An up-regulation of the atrogin-1 gene while a down regulation of the KATP channel subunits genes is observed in SOL. The co-incubation of the muscles with staurosporine+diazoxide for 24 hrs. fully prevented the reduction of the fibers diameter and protein content, and reduction of the KATP channel activity. Our data indicate that staurosporine blocks KATP channels in skeletal muscle leading to muscle atrophy and these effects are phenotype dependent.