A role for PLCβ1 in myotonic dystrophies type 1 and 2

Phosphoinositide-phospholipase C beta 1 (PLC beta 1) plays a crucial role in the initiation of the genetic program responsible for muscle differentiation. We previously demonstrated that nuclear PLC beta 1 activates the cyclin D3 promoter during the differentiation of myoblasts to myotubes, indicating that PLC beta 1 is essential for cyclin D3 promoter activation and gene transcription, through c-jun/AP1. Myotonic dystrophy (DM) is the most prevalent form of muscular dystrophy in adults. DM type 1 (DM1) and type 2 (DM2) are dominantly inherited multisystem disorders. DM1 is triggered by the pathological expansion of a (CTG)(n) triplet repeat in the gene coding for DMPK, the dystrophia myotonica-protein kinase, whereas a (CCTG)(n) tetranucleotide repeat expansion in the ZNF9 gene, encoding a CCHC-type zinc finger protein, causes DM2. We found that, unlike in normal myotubes, the level of expression of PLC beta 1 in DM1 and DM2 cells was already elevated in proliferating cells. Treatment with insulin induced a dramatic decrease in the amount of PLC beta 1. During differentiation, cyclin D3 and myogenin were elevated in normal myotubes, whereas differentiating DM1 and DM2 cells did not increase these proteins. Forced expression of PLC beta 1 in DM1 and DM2 cells increased the expression of differentiation markers, myogenin and cyclin D3, and enhanced fusion of DM myoblasts. These results highlight again that PLC beta 1 expression is a key player in myoblast differentiation, functioning as a positive regulator in the correction of delayed differentiation of skeletal muscle in DM human myoblasts.-Faenza, I., Blalock, W., Bavelloni, A., Schoser, B., Fiume, R., Pacella, S., Piazzi, M., D'Angelo, A., Cocco, L. A role for PLC beta 1 in myotonic dystrophies type 1 and 2. FASEB J. 26, 3042-3048 (2012). www.fasebj.org