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Abstract：
Duchenne and Becker muscular dystrophies are the most common muscle diseases and are both currently incurable. They are caused by mutations in the dystrophin gene, which lead to the absence or reduction/truncation of the encoded protein, with progressive muscle degeneration that clinically manifests in muscle weakness, cardiac and respiratory involvement and early death. The limits of animal models to exactly reproduce human muscle disease and to predict clinically relevant treatment effects has prompted the development of more accurate in vitro skeletal muscle models. However, the challenge of effectively obtaining mature skeletal muscle cells or satellite stem cells as primary cultures has hampered the development of in vitro models. Here, we discuss the recently developed technologies that enable the differentiation of skeletal muscle from human induced pluripotent stem cells (iPSCs) of Duchenne and Becker patients. These systems recapitulate key disease features including inflammation and scarce regenerative myogenic capacity that are partially rescued by genetic and pharmacological therapies and can provide a useful platform to study and realize future therapeutic treatments. Implementation of this model also takes advantage of the developing genome editing field, which is a promising approach not only for correcting dystrophin, but also for modulating the underlying mechanisms of skeletal muscle development, regeneration and disease. These data prove the possibility of creating an accurate Duchenne and Becker in vitro model starting from iPSCs, to be used for pathogenetic studies and for drug screening to identify strategies capable of stopping or reversing muscular dystrophinopathies and other muscle diseases.
摘要：
Duchenne和Becker肌营养不良是最常见的肌肉疾病，目前都无法治愈。它们是由肌营养不良蛋白基因突变引起的，导致编码蛋白质的缺失或减少/截短，进行性肌肉退化在临床上表现为肌肉无力，心脏和呼吸道受累和早期死亡。动物模型在精确复制人类肌肉疾病和预测临床相关治疗效果方面的局限性促使开发了更准确的体外骨骼肌模型。然而,有效获得成熟骨骼肌细胞或卫星干细胞作为原代培养物的挑战阻碍了体外模型的发展。这里,我们讨论了最近开发的能够从Duchenne和Becker患者的人诱导多能干细胞（iPSCs）分化骨骼肌的技术。这些系统概括了关键的疾病特征，包括炎症和稀缺的再生生肌能力，这些特征部分通过遗传和药物治疗得以挽救，并且可以提供有用的平台来研究和实现未来的治疗性治疗。该模型的实现还利用了不断发展的基因组编辑领域，这不仅是纠正肌营养不良蛋白的一种有前途的方法，而且还用于调节骨骼肌发育的潜在机制，再生和疾病。这些数据证明了从iPSC开始创建准确的Duchenne和Becker体外模型的可能性，用于病因学研究和药物筛选，以确定能够阻止或逆转肌营养不良蛋白病和其他肌肉疾病的策略。
