Interleukin-6 Induces Erbbs Receptor Phosphorylation And Utrophin Expression In Dystrophic Myotubes.

Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene, leading to skeletal muscle fiber loss. A promising pharmacological treatment aims to increase the level of utrophin, a functional dystrophin homolog that could compensate dystrophin absence in DMD muscle fibers. It has been described that interleukin‐6 (IL‐6) and neuregulin‐1 (NRG‐1) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL‐6, NRG‐1 and utrophin, in normal (C57) and dystrophic ( mdx ) skeletal muscle cells. Using Western Blot and semiquantitative PCR, we demonstrated that IL‐6 (100 ng/ml) induces NRG‐1 receptor phosphorylation (ErbB2/ErbB3) in both cellular types, and a transient increase on utrophin mRNA levels in dystrophic myotubes. We observed that BAPTA‐AM (an intracellular Ca 2+ chelator), GM6001 (a general metalloproteinase inhibitor), genistein (a general protein tyrosine kinase inhibitor) and PD‐158780 (an ErbB receptor tyrosine kinase inhibitor) treatment abolished utrophin mRNA induction. Our results suggest that IL‐6 induces utrophin expression in dystrophic myotubes, through NRG‐1/ErbBs signaling activation, elicited by proteolytic processing of NRG‐1 and ErbBs phosphorylation. Understanding the mechanism involved on utrophin up regulation could help to the development of DMD new therapies. FONDECYT 11100267