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.
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。