Depolarization induced slow calcium transients stimulate Neuregulin‐1β expression in dystrophic skeletal muscle cell lines

Duchenne muscular dystrophy is a neuromuscular disease originated by mutations in the dystrophin gene. Neuregulin‐1 (NRG‐1) is a growth factor that induces utrophin, a dystrophin homolog, expression. NRG‐1β is one of 150 differentially expressed genes in dystrophic (RCDMD) human skeletal muscle cells after electrical stimulation (ES; 400 pulses, 1 ms, 45 Hz). ES increases NRG‐1β mRNA and protein levels in RCDMD cells, but has no effect on normal cells. We investigated the involvement of Ca 2+ and PKC isoforms on NRG‐1β expression in electrically stimulated RCDMD cells. NRG‐1β gene expression was inhibited in the presence of the intracellular Ca 2+ chelator BAPTA‐AM, and by inhibitors of IP3‐dependent slow Ca 2+ transients as 2 APB, Ly 294002 and xestospongin B. Ryanodine, a fast Ca 2+ signal inhibitor, had no effect. Both BIM VI (general inhibitor of PKC isoforms) and Gö 6976 (specific inhibitor of Ca 2+ dependent PKC isoforms) abolished NRG‐1β mRNA induction. Our results suggest that slow Ca 2+ signals stimulate NRG‐1β transcription in RCDMD cells after depolarization, and that a Ca 2+ dependent PKC isoform is needed for activation of NRG‐1β expression. Since utrophin can partly compensate dystrophin disfunction, knowledge on the mechanism involved on NRG‐1 up regulation could help development of new therapies. PSD24, FONDAP 15010006, FONDECYT 11100267