ABSTRACT 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.

中文翻译：

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Emery-Dreifuss 肌营养不良症中 TGF β2 血清水平升高：对肌细胞和肌腱细胞分化和纤维化过程的影响

摘要 在由 LMNA 基因突变引起的罕见疾病中，Emery-Dreifuss 肌营养不良症 2 型和肢带型肌营养不良症 1B 的特征是肌肉无力和消瘦、关节挛缩、心肌病伴传导系统障碍。尚未确定这些病理的循环生物标志物。在这里，我们分析了一组受这些肌肉筋膜病影响的患者的分泌组，以试图确定一个共同的特征。多重细胞因子分析表明，绝大多数受检患者的转化生长因子 β2（TGF β2）和白细胞介素 17 血清水平持续升高，而白细胞介素 6 和碱性成纤维细胞生长因子在患者亚组中发生改变。TGF β2 的水平也在从患者活组织检查建立的成纤维细胞和成肌细胞培养物中以及来自携带导致人类 Emery-Dreifuss 肌营养不良症的 H222P Lmna 突变的小鼠的血清中增加。患者血清和成纤维细胞条件培养基均可激活正常人成肌细胞和肌腱细胞中的 TGF β2 依赖性成纤维程序并抑制成肌细胞分化。与这些结果一致，TGF β2 中和抗体避免了纤维化标记物激活和肌生成障碍。还在椎板病变细胞中确定了细胞内在的 TGF β2 依赖性机制，其中 TGF β2 激活了 AKT/mTOR 磷酸化。这些数据表明，TGF β2 有助于 Emery-Dreifuss 肌营养不良症 2 型和肢带型肌营养不良症 1B 的发病机制，可被视为这些疾病的潜在生物标志物。此外，TGF β2 在肌腱细胞中的致病作用的证据提供了第一个对肌肉椎板病中关节挛缩发生的机制洞察。