Inspiratory dysfunction occurs in patients with heart failure with reduced ejection fraction (HFrEF) in a manner that depends on disease severity and by mechanisms that are not fully understood. In the current study, we tested whether HFrEF effects on diaphragm (inspiratory muscle) depend on disease severity and examined putative mechanisms for diaphragm abnormalities via global and redox proteomics. We allocated male rats into Sham, moderate (mHFrEF), or severe HFrEF (sHFrEF) induced by myocardial infarction and examined the diaphragm muscle. Both mHFrEF and sHFrEF caused atrophy in type IIa and IIb/x fibers. Maximal and twitch specific forces (N/cm2) were decreased by 19 ± 10% and 28 ± 13%, respectively, in sHFrEF (p < .05), but not in mHFrEF. Global proteomics revealed upregulation of sarcomeric proteins and downregulation of ribosomal and glucose metabolism proteins in sHFrEF. Redox proteomics showed that sHFrEF increased reversibly oxidized cysteine in cytoskeletal and thin filament proteins and methionine in skeletal muscle α-actin (range 0.5 to 3.3-fold; p < .05). In conclusion, fiber atrophy plus contractile dysfunction caused diaphragm weakness in HFrEF. Decreased ribosomal proteins and heighted reversible oxidation of protein thiols are candidate mechanisms for atrophy or anabolic resistance as well as loss of specific force in sHFrEF.

中文翻译：

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大鼠心力衰竭的肌无力和蛋白质组学（整体和氧化还原）修饰，大鼠射血分数降低。

心力衰竭患者的射血分数（HFrEF）降低会导致吸气功能障碍，具体取决于疾病的严重程度和尚不完全清楚的机制。在当前的研究中，我们测试了HFrEF对diaphragm肌（吸肌）的影响是否取决于疾病的严重程度，并通过整体和氧化还原蛋白质组学检查了diaphragm肌异常的推定机制。我们将雄性大鼠分为由心肌梗塞诱发的假，中度（mHFrEF）或重度HFrEF（sHFrEF），并检查examined肌。mHFrEF和sHFrEF均导致IIa型和IIb / x型纤维萎缩。在sHFrEF中，最大和抽搐比力（N / cm2）分别降低了19±10％和28±13％（p <.05），而在mHFrEF中则没有。全球蛋白质组学揭示了sHFrEF中肌节蛋白的上调以及核糖体和葡萄糖代谢蛋白的下调。氧化还原蛋白质组学表明，sHFrEF可增加细胞骨架和细丝蛋白中的可逆氧化半胱氨酸以及骨骼肌α-肌动蛋白中的甲硫氨酸（范围为0.5至3.3倍； p <.05）。总之，纤维萎缩加收缩功能障碍导致HFrEF的diaphragm肌无力。核糖体蛋白的减少和蛋白硫醇的高度可逆氧化是导致sHFrEF萎缩或合成代谢抵抗以及比力丧失的候选机制。总之，纤维萎缩加收缩功能障碍导致HFrEF的diaphragm肌无力。核糖体蛋白的减少和蛋白硫醇的高度可逆氧化是导致sHFrEF萎缩或合成代谢抵抗以及比力丧失的候选机制。总之，纤维萎缩加收缩功能障碍导致HFrEF的diaphragm肌无力。核糖体蛋白的减少和蛋白硫醇的高度可逆氧化是导致sHFrEF萎缩或合成代谢抵抗以及比力丧失的候选机制。