Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U1258, Université de Strasbourg, 67404, Illkirch, France.
Brain. 2023 Oct 3;146(10):4158-4173. doi: 10.1093/brain/awad251.
Centronuclear and myotubular myopathies (CNM) are rare and severe genetic diseases associated with muscle weakness and atrophy as well as intracellular disorganization of myofibres. The main mutated proteins control lipid and membrane dynamics and are the lipid phosphatase myotubularin (MTM1), and the membrane remodelling proteins amphiphysin 2 (BIN1) and dynamin 2 (DNM2). There is no available therapy. Here, to validate a novel therapeutic strategy for BIN1- and DNM2-CNM, we evaluated adeno-associated virus-mediated MTM1 (AAV-MTM1 ) overexpression in relevant mouse models. Early systemic MTM1 overexpression prevented the development of the CNM pathology in Bin1mck-/- mice, while late intramuscular MTM1 expression partially reverted the established phenotypes after only 4 weeks of treatment. However, AAV-MTM1 injection did not change the DNM2-CNM mouse phenotypes. We investigated the mechanism of the rescue of the myopathy in BIN1-CNM and found that the lipid phosphatase activity of MTM1 was essential for the rescue of muscle atrophy and myofibre hypotrophy but dispensable for the rescue of myofibre disorganization including organelle mis-position and T-tubule defects. Furthermore, the improvement of T-tubule organization correlated with normalization of key regulators of T-tubule morphogenesis, dysferlin and caveolin. Overall, these data support the inclusion of BIN1-CNM patients in an AAV-MTM1 clinical trial.
中心核肌病和肌小管肌病（CNM）是罕见且严重的遗传性疾病，与肌肉无力和萎缩以及肌纤维内的细胞内紊乱有关。主要突变蛋白控制脂质和膜动力学，是脂质磷酸酶肌小管素（MTM1），以及膜重塑蛋白 amphiphysin 2（BIN1）和 dynamin 2（DNM2）。目前尚无可用的治疗方法。在这里，为了验证 BIN1 和 DNM2-CNM 的新治疗策略，我们评估了腺相关病毒介导的 MTM1（AAV-MTM1）过表达在相关小鼠模型中的作用。早期全身 MTM1 过表达可预防 Bin1mck-/- 小鼠的 CNM 病理发生，而晚期肌肉内 MTM1 表达仅在治疗 4 周后即可部分逆转已建立的表型。然而，AAV-MTM1 注射并未改变 DNM2-CNM 小鼠的表型。我们研究了 BIN1-CNM 肌病挽救的机制，发现 MTM1 的脂质磷酸酶活性对于肌肉萎缩和肌纤维萎缩的挽救是必需的，但对于肌纤维紊乱的挽救是可有可无的，包括细胞器位置异常和 T 小管缺陷。此外，T 小管组织的改善与 T 小管形态发生的关键调节因子 dysferlin 和 caveolin 的正常化相关。总的来说，这些数据支持将 BIN1-CNM 患者纳入 AAV-MTM1 临床试验。
