Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy-derived cells

Abstract

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) drive calcium signals involved in skeletal muscle excitation-transcription coupling and plasticity; IP3R subtype distribution and downstream events evoked by their activation have not been studied in human muscle nor has their possible alteration in Duchenne muscular dystrophy (DMD). We studied the expression and localization of IP3R subtypes in normal and DMD human muscle and in normal (RCMH) and dystrophic (RCDMD) human muscle cell lines. In normal muscle, both type 1 IP3Rs (IP3R1) and type 2 IP3Rs (IP3R2) show a higher expression in type II fibers, whereas type 3 IP3Rs (IP3R3) show uniform distribution. In DMD biopsies, all fibers display a homogeneous IP3R2 label, whereas 24 ± 7% of type II fibers have lost the IP3R1 label. RCDMD cells show 5-fold overexpression of IP3R2 and down-regulation of IP3R3 compared with RCMH cells. A tetanic stimulus induces IP 3-dependent slow Ca2+ transients significantly larger and faster in RCDMD ce