García-Puga Mikel, Gerenu Gorka, Bargiela Ariadna, Espinosa-Espinosa Jorge, Mosqueira-Martín Laura, Sagartzazu-Aizpurua Maialen, Aizpurua Jesús M, Vallejo-Illarramendi Ainara, Artero Rubén, López de Munain Adolfo, Matheu Ander
Cellular Oncology Group, Biogipuzkoa Health Research Institute, Paseo Dr. Beguiristain s/n, 20014 San Sebastian, Spain.
Neuroscience Area, Biogipuzkoa Health Research Institute, Biodonostia Institute, 20014 San Sebastian, Spain.
Cells. 2024 Nov 22;13(23):1939. doi: 10.3390/cells13231939.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder clinically characterized by progressive muscular weakness and multisystem degeneration, which correlates with the size of CTG expansion and MBLN decrease. These changes induce a calcium and redox homeostasis imbalance in several models that recapitulate the features of premature tissue aging. In this study, we characterized the impact of a new family of FKBP12 ligands (generically named MPs or MP compounds) designed to stabilize FKBP12 binding to the ryanodine receptors and normalize calcium dysregulation under oxidative stress. Human primary fibroblasts from DM1 patients and control donors, treated with MP compounds or not, were used for functional studies of cell viability, proliferation, and metabolism. The gene expression profile in treated cells was determined using RNA sequencing. The impact of MP compounds in vivo was evaluated in a model of the disease using locomotor activity and longevity studies. The treatment with different MP compounds reversed oxidative stress and impaired cell viability and proliferation, mitochondrial activity, and metabolic defects in DM1-derived primary fibroblasts. RNA sequencing analysis confirmed the restoration of molecular pathways related to calcium and redox homeostasis and additional pathways, including the cell cycle and metabolism. This analysis also revealed the rescue of alternative splicing events in DM1 fibroblasts treated with MP compounds. Importantly, treatment with MP compounds significantly extended the lifespan and improved the locomotor activity of a model of the DM1 disease, and restored molecular defects characteristic of the disease in vivo. Our results revealed that MP compounds rescue multiple premature aging phenotypes described in DM1 models and decipher the benefits of this new family of compounds in the pre-clinical setting of DM1.
1型强直性肌营养不良（DM1）是一种常染色体显性疾病，临床特征为进行性肌肉无力和多系统退化，这与CTG重复序列的大小及肌盲蛋白（MBLN）减少相关。在多种重现过早组织衰老特征的模型中，这些变化会导致钙和氧化还原稳态失衡。在本研究中，我们对一类新的FKBP12配体（统称为MPs或MP化合物）的作用进行了表征，这类配体旨在稳定FKBP12与兰尼碱受体的结合，并在氧化应激下使钙调节异常恢复正常。来自DM1患者和对照供体的人原代成纤维细胞，无论是否用MP化合物处理，都用于细胞活力、增殖和代谢的功能研究。使用RNA测序确定处理后细胞中的基因表达谱。通过运动活性和寿命研究，在疾病模型中评估MP化合物在体内的作用。用不同的MP化合物处理可逆转氧化应激，并改善DM1来源的原代成纤维细胞中受损的细胞活力、增殖、线粒体活性和代谢缺陷。RNA测序分析证实了与钙和氧化还原稳态相关的分子途径以及包括细胞周期和代谢在内的其他途径得以恢复。该分析还揭示了用MP化合物处理的DM1成纤维细胞中可变剪接事件得到了挽救。重要的是，用MP化合物处理可显著延长DM1疾病模型的寿命并改善其运动活性，并在体内恢复该疾病的特征性分子缺陷。我们的结果表明，MP化合物可挽救DM1模型中描述的多种过早衰老表型，并阐明了这类新化合物在DM1临床前研究中的益处。
