Garros Roser Farre, Paul Richard, Connolly Martin, Lewis Amy, Garfield Benjamin E, Natanek S Amanda, Bloch Susannah, Mouly Vincent, Griffiths Mark J, Polkey Michael I, Kemp Paul R
1 Molecular Medicine Section and.
2 National Institute for Health Research Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, United Kingdom; and.
Am J Respir Crit Care Med. 2017 Dec 1;196(11):1422-1433. doi: 10.1164/rccm.201701-0101OC.
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.
To identify microRNAs (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.
miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-β signaling in vitro and in vivo.
miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (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 transforming growth factor-β signaling. In mice, miR-542 overexpression caused muscle wasting, and 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 transforming growth factor-β signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery.
Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
骨骼肌质量和功能的丧失是危重病和一系列慢性疾病的常见后果，但其发生机制尚不清楚。
鉴定肌肉萎缩患者股四头肌中上调的微小RNA（miRNA），并确定它们导致肌肉功能障碍的分子途径。
对慢性阻塞性肺疾病患者和重症监护病房获得性肌无力（ICUAW）患者的股四头肌中的miRNA-542-3p/5p（miR-542-3p/5p）进行定量分析。在体外和体内确定miR-542-3p/5p对线粒体功能和转化生长因子-β信号传导的影响。
慢性阻塞性肺疾病患者中miR-542-3p/5p升高，但在ICUAW患者中更为明显。在体外，miR-542-3p抑制线粒体核糖体蛋白MRPS10的表达并降低12S核糖体RNA（rRNA）表达，提示线粒体核糖体应激。miR-542-5p增加核磷酸化SMAD2/3并抑制SMAD7、SMURF1和PPP2CA的表达，这些蛋白可抑制或减少SMAD2/3磷酸化，提示miR-542-5p增加转化生长因子-β信号传导。在小鼠中，miR-542过表达导致肌肉萎缩，并降低线粒体功能、12S rRNA表达和SMAD7表达，这与miRNA在体外的作用一致。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转化生长因子-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水平与术后肌肉损失呈正相关。
miR-542-3p/5p升高可能通过促进线粒体功能障碍和激活SMAD2/3磷酸化导致重症监护病房患者肌肉萎缩。
