Intra-cardiac transplantation of undifferentiated skeletal muscle cells (myoblasts) has emerged as a promising therapy for myocardial infarct repair and is already undergoing clinical trials. The fact that cells originating from skeletal muscle have different electrophysiological properties than cardiomyocytes, however, may considerably limit the success of this therapy and, in addition, cause side effects. Indeed, a major problem observed after myoblast transplantation is the occurrence of ventricular arrhythmias. The most often transient nature of these arrhythmias may suggest that, once transplanted into cardiac tissue, skeletal muscle cells adopt more cardiac-like electrophysiological properties. To test if a cardiac cell environment can indeed modify electrophysiological parameters of skeletal muscle cells, we treated mouse C2C12 myocytes with differentiation medium preconditioned by primary cardiocytes and compared their functional sodium current properties with those of control cells. We found this treatment to significantly alter the activation and inactivation properties of sodium currents from "skeletal muscle"- to more "cardiac"-like ones. Sodium currents of cardiac-conditioned cells showed a reduced sensitivity to block by tetrodotoxin. These findings and reverse transcription PCR experiments suggest that an up-regulation of the expression of the cardiac sodium channel isoform Na_v1.5 versus the skeletal muscle isoform Na_v1.4 is responsible for the observed changes in sodium current function. We conclude that cardiomyocytes alter sodium channel isoform expression of skeletal muscle cells via a paracrine mechanism. Thereby, skeletal muscle cells with more cardiac-like sodium current properties are generated.