Angelini Giuseppe, Capra Emanuele, Rossi Francesca, Mura Giada, Saclier Marielle, Taglietti Valentina, Rovetta Gabriele, Epis Raffaele, Careccia Giorgia, Bonfanti Chiara, Messina Graziella
Department of Biosciences, University of Milan, 20133 Milan, Italy.
iScience. 2023 Dec 10;27(1):108696. doi: 10.1016/j.isci.2023.108696. eCollection 2024 Jan 19.
Muscular dystrophies (MDs) are incurable genetic myopathies characterized by progressive degeneration of skeletal muscles. Dystrophic mice lacking the transcription factor Nfix display morphological and functional improvements of the disease. Recently, we demonstrated that MAPK signaling pathway positively regulates Nfix in muscle development and that Cyanidin, a natural antioxidant molecule, strongly ameliorates the pathology. To explore a synergistic approach aimed at treating MDs, we administered Trametinib, a clinically approved MEK inhibitor, alone or combined with Cyanidin to adult null mice. We observed that chronic treatment with Trametinib and Cyanidin reduced Nfix in myogenic cells but, unexpectedly, caused ectopic calcifications exclusively in dystrophic muscles. The combined treatment with Cyanidin resulted in histological improvements by preventing Trametinib-induced calcifications in Diaphragm and Soleus. Collectively, this first pilot study revealed that Nfix is modulated by the MAPK pathway in MDs, and that Cyanidin partly rescued the unexpected ectopic calcifications caused by MEK inhibition.
肌肉萎缩症（MDs）是一种无法治愈的遗传性肌病，其特征是骨骼肌进行性退化。缺乏转录因子Nfix的营养不良小鼠表现出疾病的形态和功能改善。最近，我们证明丝裂原活化蛋白激酶（MAPK）信号通路在肌肉发育中正向调节Nfix，并且花青素（一种天然抗氧化分子）能显著改善病理状况。为了探索一种旨在治疗MDs的协同方法，我们将曲美替尼（一种临床批准的MEK抑制剂）单独或与花青素联合给予成年Nfix基因敲除小鼠。我们观察到，曲美替尼和花青素的长期治疗降低了成肌细胞中的Nfix，但出乎意料的是，仅在营养不良的肌肉中导致了异位钙化。花青素联合治疗通过预防曲美替尼诱导的膈肌和比目鱼肌钙化，带来了组织学改善。总体而言，这项初步的先导研究表明，MDs中Nfix受MAPK通路调节，并且花青素部分挽救了由MEK抑制引起的意外异位钙化。
