期刊
NUCLEUS
卷 9, 期 1, 页码 292-304出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/19491034.2018.1467722
关键词
Laminopathies; LMNA gene; lamin A/C; Emery-Dreifuss Muscular Dystrophy type 2 (EDMD2); Limb-Girdle muscular Dystrophy 1B (LGMD1B); Dilated Cardiomyopathy (CMD1A); Transforming growth factor beta 2 (TGF beta 2); tendon fibrosis; muscle fibrosis; muscular differentiation
类别
资金
- AIDMED onlus and Alessandra Proietti onlus
- Italian MIUR PRIN
- Fondazione Del Monte di Bologna e Ravenna
- IOR 5 per mille project
- COST Action [CA15214]
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 2) 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 2 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 2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF 2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF 2-dependent mechanisms were also determined in laminopathic cells, where TGF 2 activated AKT/mTOR phosphorylation. These data show that TGF 2 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 2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
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