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Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：我们最近报道了Musashi2（MSI2）蛋白在罕见的神经肌肉疾病肌强直性肌营养不良1型中的上调，通过降低miR-7水平促进肌肉分解代谢过程自噬和UPS的过度激活。由于油酸（OA）是miR-7生物发生中MSI2活性的已知变构调节因子，因此我们试图评估该脂肪酸的内源性水平及其在体外挽救细胞分化表型中的治疗潜力。在这项工作中,来自DM1患者的四种肌肉细胞系接受OA治疗24小时，并对自噬和肌肉分化参数进行分析。
结果：我们证明了不同细胞模型中OA水平的降低。OA补充拯救疾病相关表型，如融合指数，肌管直径，抑制自噬。这涉及抑制MSI2调节直接分子靶标miR-7，因为OA异裂体，反油酸（EA）不能引起相同的救援。OA水平的降低似乎源于生物发生受损，因为硬脂酰辅酶A去饱和酶1（SCD1）的水平，负责将硬脂酸转化为油酸，在DM1中减少，并与OA量相关。
结论：在DM1中，我们首次描述了脂肪酸代谢障碍，至少在某种程度上,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>自噬轴解释肌肉萎缩表型。
结果：我们证明了不同细胞模型中OA水平的降低。OA补充拯救疾病相关表型，如融合指数，肌管直径，抑制自噬。这涉及抑制MSI2调节直接分子靶标miR-7，因为OA异裂体，反油酸（EA）不能引起相同的救援。OA水平的降低似乎源于生物发生受损，因为硬脂酰辅酶A去饱和酶1（SCD1）的水平，负责将硬脂酸转化为油酸，在DM1中减少，并与OA量相关。
结论：在DM1中，我们首次描述了脂肪酸代谢障碍，至少在某种程度上,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>自噬轴解释肌肉萎缩表型。
