1. Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes
- Author
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Nicola Carboni, Chiara Lanzuolo, Elisa Schena, Lucio Santoro, Tiziana Mongini, Elena Biagini, Lucia Morandi, Gisèle Bonne, Giovanna Lattanzi, Lorenzo Maggi, Patrizia Sabatelli, Giulia Ricci, Lucia Ruggiero, Cristina Cappelletti, Marta Columbaro, Luisa Politano, Antoine Muchir, Giuseppe Boriani, Camilla Evangelisti, Sabino Prencipe, Gabriele Siciliano, Elena Pegoraro, Pia Bernasconi, Paola Cavalcante, Liliana Vercelli, Carmelo Rodolico, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Pisa - Università di Pisa, Second University of Naples-Caserta, University of Naples Federico II, University of Turin, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Università degli Studi di Modena e Reggio Emilia, Universita degli Studi di Padova, Istituto Nazionale Genetica Molecolare [Milano] (INGM), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Bernasconi, Pia, Carboni, Nicola, Ricci, Giulia, Siciliano, Gabriele, Politano, Luisa, Maggi, Lorenzo, Mongini, Tiziana, Vercelli, Liliana, Rodolico, Carmelo, Biagini, Elena, Boriani, Giuseppe, Ruggiero, Lucia, Santoro, Lucio, Schena, Elisa, Prencipe, Sabino, Evangelisti, Camilla, Pegoraro, Elena, Morandi, Lucia, Columbaro, Marta, Lanzuolo, Chiara, Sabatelli, Patrizia, Cavalcante, Paola, Cappelletti, Cristina, Bonne, Gisèle, Muchir, Antoine, Lattanzi, Giovanna, Bernasconi P., Carboni N., Ricci G., Siciliano G., Politano L., Maggi L., Mongini T., Vercelli L., Rodolico C., Biagini E., Boriani G., Ruggiero L., Santoro L., Schena E., Prencipe S., Evangelisti C., Pegoraro E., Morandi L., Columbaro M., Lanzuolo C., Sabatelli P., Cavalcante P., Cappelletti C., Bonne G., Muchir A., and Lattanzi G.
- Subjects
0301 basic medicine ,Male ,Basic fibroblast growth factor ,LMNA ,chemistry.chemical_compound ,Mice ,Transforming growth factor beta 2 (TGF b2) ,Medicine ,Muscular Dystrophy ,Muscular dystrophy ,Emery–Dreifuss muscular dystrophy ,LMNA gene ,Cells, Cultured ,lamin A/C ,muscle fibrosis ,Mice, Knockout ,Cultured ,tendon fibrosis ,biology ,Myogenesis ,Emery-Dreifuss ,Cell Differentiation ,Middle Aged ,Muscular Dystrophy, Emery-Dreifuss ,3. Good health ,Laminopathie ,Transforming growth factor beta 2 (TGF β2) ,Fibroblast ,Female ,Interleukin 17 ,Human ,musculoskeletal diseases ,Adult ,Cells ,Knockout ,Muscle Cell ,Dilated Cardiomyopathy (CMD1A) ,Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2) ,Laminopathies ,Limb-Girdle muscular Dystrophy 1B (LGMD1B) ,muscular differentiation ,03 medical and health sciences ,Transforming Growth Factor beta2 ,Young Adult ,Lamin A/C ,Muscle fibrosis ,Muscular differentiation ,Tendon fibrosis ,Animals ,Fibroblasts ,Humans ,Muscle Cells ,Tenocytes ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Interleukin 6 ,Animal ,Muscular Dystrophy, Emery-Dreifu ,business.industry ,muscle fibrosi ,Cell Biology ,Transforming growth factor beta ,Tenocyte ,medicine.disease ,030104 developmental biology ,chemistry ,biology.protein ,Cancer research ,business ,Tendon fibrosi ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
- Published
- 2018