Emery-Dreifuss muscular dystrophy is associated with mutations in LMNA and in its partner genes. More than one pathogenetic pathway has been suggested for the disease, including altered chromatin regulation and gene expression, defective cellular signaling and altered positioning of myonuclei during differentiation. A systemic effect of LMNA mutations has been suggested in recent studies. In the reported study, the secretory profile of Emery-Dreifuss Muscular Dystrophy (EDMD) fibroblasts and serum levels of cytokines were measured by multiple approaches including real time quantitative PCR, ELISA and multiplex ELISA array testing. Elevated TGFbeta2 levels were detected in sera from a cohort of unrelated EDMD2 patients bearing different LMNA mutations and in conditioned culture media from EDMD2 fibroblasts. To test the biological relevance of increased TGFbeta2 secretion, we performed co-culture experiments using EDMD2 fibroblasts and murine C2C12 myoblasts. Decreased differentiation rate was observed in myoblasts conditioned with EDMD2 medium with respect to controls. Moreover, a neutralizing anti-TGFbeta antibody administered to co-cultured cells rescued the differentiation rate of C2C12 myoblasts. These data suggest that TGFbeta2 contributes to the pathogenetic mechanism of EDMD2.
TGFbeta 2 levels are elevated in Emery-Dreifuss muscular dystrophy: effects on muscle differentiation.
Giovanna Lattanzi
2014
Abstract
Emery-Dreifuss muscular dystrophy is associated with mutations in LMNA and in its partner genes. More than one pathogenetic pathway has been suggested for the disease, including altered chromatin regulation and gene expression, defective cellular signaling and altered positioning of myonuclei during differentiation. A systemic effect of LMNA mutations has been suggested in recent studies. In the reported study, the secretory profile of Emery-Dreifuss Muscular Dystrophy (EDMD) fibroblasts and serum levels of cytokines were measured by multiple approaches including real time quantitative PCR, ELISA and multiplex ELISA array testing. Elevated TGFbeta2 levels were detected in sera from a cohort of unrelated EDMD2 patients bearing different LMNA mutations and in conditioned culture media from EDMD2 fibroblasts. To test the biological relevance of increased TGFbeta2 secretion, we performed co-culture experiments using EDMD2 fibroblasts and murine C2C12 myoblasts. Decreased differentiation rate was observed in myoblasts conditioned with EDMD2 medium with respect to controls. Moreover, a neutralizing anti-TGFbeta antibody administered to co-cultured cells rescued the differentiation rate of C2C12 myoblasts. These data suggest that TGFbeta2 contributes to the pathogenetic mechanism of EDMD2.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
