Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.

中文翻译：

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miR-542 促进线粒体功能障碍和 SMAD 活性，并在 ICU 获得性虚弱中升高

理由：骨骼肌质量和功能的丧失是危重疾病和一系列慢性疾病的常见后果，但其发生的机制尚不清楚。目的：我们旨在鉴定肌肉萎缩患者股四头肌中增加的 miRNA，并确定它们导致肌肉功能障碍的分子途径。方法：在 COPD 和重症监护病房获得性虚弱 (ICUAW) 患者的股四头肌中定量 miR-542-3p/-5p。在体外和体内测定了 miR-542-3p/5p 对线粒体功能和 TGF-β 信号传导的影响。测量和主要结果： miR-542-3p/5p 在 COPD 患者中升高，但在 ICUAW 患者中更显着。在体外，miR-542-3p 抑制线粒体核糖体蛋白 MRPS10 的表达，并减少 12S rRNA 表达，表明线粒体核糖体应激。miR-542-5p 增加核磷酸化 SMAD2/3 并抑制 SMAD7、SMURF1 和 PPP2CA 的表达，这些蛋白质抑制或减少 SMAD2/3 磷酸化表明 miR-542-5p 增加了 TGF-β 信号传导。在小鼠中，miR-542 过表达导致肌肉萎缩、线粒体功能降低、12S rRNA 表达和 SMAD7 表达，与体外 miRNA 的作用一致。同样，在 ICUAW 患者中，12S rRNA 和 SMAD2/3 磷酸化抑制剂的表达降低，表明线粒体核糖体应激和 TGF-β 信号传导增加。在接受主动脉手术的患者中，术前 miR-542-3p/5p 水平与手术后肌肉损失呈正相关。结论;