Myocytes from congenital Myotonic Dystrophy display abnormal Na+ channel activities

Myotonic dystrophy (DM1) is an inherited neuromuscular disease caused by an expansion of a CTG repeat located in the untranslated region of the DMPK gene.One of the hallmarks of the disease is increased excitability and delayed relaxation of muscle. Electrophysiologically, an abnormal tendency to fire repetitive action potentials has been found in DM1 muscles. The trans-dominant effect of the mutant mRNA leads to aberrant splicing of the muscle-specific chloride channel pre-mRNA and a significant reduction of chloride channel expression in DM1 muscles that may play a critical role in DM1 membrane hyperexcitability. In addition, impairments in the Ca2+-dependent K+ channels SK3 and sodium channels have also been described in DM1 muscles. Cell-attached patch-clamp experiments performed on fiber segments isolated from DM1 patients have revealed late openings of the Na+ channels, and delayed activation–inactivation properties of the Na+ currents have been described in DM1 myoballs.Even if direct demonstration of Na+ channel phosphorylation by myotonic dystrophy protein kinase (DMPK) has not yet occurred, different reports have supported a possible regulation of the Na+ channels by DMPK activity. The activity of the Na+ channels has never been investigated in myoblasts isolated from congenital DM1, a more severe form of DM1 with reduced DMPK protein.In this study, we have examined the biophysical properties of the macroscopic Na+ currents in mononucleated myocytes from congenital DM1 at the onset of fusion.