Elevated TGFbeta 2 levels in Emery-Dreifuss muscular dystrophy affect myocyte and tenocyte phenotype and favor the fibrogenic process

Emery-Dreifuss Muscular Dystrophy and Dilated Cardiomyopathy with conduction system disorders are rare muscular diseases associated with LMNA mutations. We have previously observed altered TGFbeta 2 secretion in cells and serum from Mandibuloacral Dysplasia, a rare progeroid laminopathy. Here, we performed a study in a cohort of laminopathic patients affected by muscular laminopathies to investigate serum levels of TGFbeta 2, secretion of TGFbeta 2 in cultured fibroblasts and myoblasts and establish a correlation between phenotype and cytokine amount. Multiplex cytokine assay showed that TGFbeta 2 is consistently elevated in the vast majority of Emery-Dreifuss muscular dystrophy sera, while other cytokines including IL17, IL6 and bFGF are altered in subgroups of patients. Here, we analyzed the effect of laminopathic sera and conditioned media on tenocyte and myoblast proliferation and activation of pro-fibrotic genes as well as on cell differentiation. Both patient serum and Emery-Dreifuss fibroblast-conditioned media activated a fibrogenic program both in myoblasts and in tenocytes and inhibited myoblast and tenocyte differentiation. The effect was dependent on TGFbeta 2 and could be reverted by using a specific neutralizing antibody. These data show that modulation of TGFbeta 2 secretion and activity is a promising therapeutic approach for muscular laminopathies.