Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes

Autor: 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
Přispěvatelé: 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., Lattanzi G.
Jazyk: angličtina
Rok vydání: 2018
Předmět:
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
Zdroj: Nucleus
Nucleus, Taylors and Francis, 2018, 9 (1), pp.337-349. ⟨10.1080/19491034.2018.1467722⟩
ISSN: 1949-1042
1949-1034
DOI: 10.1080/19491034.2018.1467722⟩
Popis: 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.
Databáze: OpenAIRE
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