成人最常见的肌营养不良是强直性肌营养不良1型(DM1),一种以肌强直为特征的常染色体显性疾病,肌肉萎缩和虚弱,和多系统功能障碍。这种疾病是由CTG三联体在DMPK基因的异常扩增引起的,当转录成扩增的mRNA时,可以导致RNA毒性功能的获得,替代拼接损伤,以及不同信号通路的功能障碍,许多由蛋白质磷酸化调节。为了深入表征DM1中的蛋白质磷酸化改变,通过PubMed和WebofScience数据库进行了系统综述。从总共962篇文章中筛选,包括41个进行定性分析,在那里我们检索到了蛋白激酶总水平和磷酸化水平的信息,蛋白磷酸酶,DM1人类样本以及动物和细胞模型中的磷蛋白。29种激酶,3种磷酸酶,据报道,DM1中17种磷蛋白发生了改变。调节细胞功能的信号通路,如葡萄糖代谢,细胞周期,肌生成,细胞凋亡受损,从AKT/mTOR等途径的显著改变可以看出,MEK/ERK,PKC/CUGBP1,AMPK,和其他DM1样品。这解释了DM1的复杂性及其不同的表现和症状,如胰岛素抵抗和癌症风险增加。可以进行进一步的研究来补充和详细探索特定的途径以及它们在DM1中的调节是如何改变的,以找出导致这些表现的关键磷酸化改变。并最终找到未来治疗的治疗靶点。
Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic
review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.