Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), University of Valencia, Valencia, Spain.
INCLIVA Biomedical Research Institute, Valencia, Spain.
Biol Res. 2024 May 17;57(1):29. doi: 10.1186/s40659-024-00496-z.
We recently reported that upregulation of Musashi 2 (MSI2) protein in the rare neuromuscular disease myotonic dystrophy type 1 contributes to the hyperactivation of the muscle catabolic processes autophagy and UPS through a reduction in miR-7 levels. Because oleic acid (OA) is a known allosteric regulator of MSI2 activity in the biogenesis of miR-7, here we sought to evaluate endogenous levels of this fatty acid and its therapeutic potential in rescuing cell differentiation phenotypes in vitro. In this work, four muscle cell lines derived from DM1 patients were treated with OA for 24 h, and autophagy and muscle differentiation parameters were analyzed.
We demonstrate a reduction of OA levels in different cell models of the disease. OA supplementation rescued disease-related phenotypes such as fusion index, myotube diameter, and repressed autophagy. This involved inhibiting MSI2 regulation of direct molecular target miR-7 since OA isoschizomer, elaidic acid (EA) could not cause the same rescues. Reduction of OA levels seems to stem from impaired biogenesis since levels of the enzyme stearoyl-CoA desaturase 1 (SCD1), responsible for converting stearic acid to oleic acid, are decreased in DM1 and correlate with OA amounts.
For the first time in DM1, we describe a fatty acid metabolism impairment that originated, at least in part, from a decrease in SCD1. Because OA allosterically inhibits MSI2 binding to molecular targets, reduced OA levels synergize with the overexpression of MSI2 and contribute to the MSI2 > miR-7 > autophagy axis that we proposed to explain the muscle atrophy phenotype.
我们最近报道，在罕见的神经肌肉疾病 1 型肌强直性营养不良中，Musashi 2（MSI2）蛋白的上调通过降低 miR-7 水平，导致肌肉分解代谢过程自噬和 UPS 的过度激活。因为油酸（OA）是 MSI2 在 miR-7 生物发生中活性的已知变构调节剂，因此我们在此评估内源性这种脂肪酸的水平及其在体外挽救细胞分化表型的治疗潜力。在这项工作中，用 OA 处理源自 DM1 患者的四种肌细胞系 24 小时，并分析自噬和肌肉分化参数。
我们证明了疾病的不同细胞模型中 OA 水平降低。OA 补充挽救了疾病相关表型，如融合指数、肌管直径，并抑制了自噬。这涉及抑制 MSI2 对直接分子靶标 miR-7 的调节，因为 OA 同系物，反油酸（EA）不能引起相同的挽救。OA 水平的降低似乎源于生物发生受损，因为负责将硬脂酸转化为油酸的酶硬脂酰辅酶 A 去饱和酶 1（SCD1）的水平在 DM1 中降低，并且与 OA 量相关。
这是在 DM1 中首次描述脂肪酸代谢受损，至少部分源于 SCD1 的减少。因为 OA 变构抑制 MSI2 与分子靶标的结合，降低的 OA 水平与 MSI2 的过表达协同作用，并有助于我们提出的 MSI2>miR-7>自噬轴，以解释肌肉萎缩表型。
