Mangner Norman, Weikert Bettina, Bowen T Scott, Sandri Marcus, Höllriegel Robert, Erbs Sandra, Hambrecht Rainer, Schuler Gerhard, Linke Axel, Gielen Stephan, Adams Volker
Department of Internal Medicine/Cardiology, University of Leipzig-Heart Center Leipzig, Germany.
Department of Internal Medicine/Cardiology, Clinic Altenburg Altenburg, Germany.
J Cachexia Sarcopenia Muscle. 2015 Dec;6(4):381-90. doi: 10.1002/jcsm.12034. Epub 2015 Apr 30.
Chronic heart failure (CHF) results in limb and respiratory muscle weakness, which contributes to exercise intolerance and increased morbidity and mortality, yet the molecular mechanisms remain poorly understood. Therefore, we aimed to compare parameters of antioxidative capacity, energy metabolism, and catabolic/anabolic balance in diaphragm and quadriceps muscle in an animal model of CHF.
Ligation of the left anterior descending coronary artery (n = 13) or sham operation (n = 11) was performed on Wistar Kyoto rats. After 12 weeks, echocardiography and invasive determination of maximal rates of left ventricular (LV) pressure change were performed. Antioxidative and metabolic enzyme activities and expression of catabolic/anabolic markers were assessed in quadriceps and diaphragm muscle.
Ligated rats developed CHF (i.e. severe LV dilatation, reduced LV ejection fraction, and impaired maximal rates of LV pressure change; P < 0.001). There was a divergent response for antioxidant enzymes between the diaphragm and quadriceps in CHF rats, with glutathione peroxidase and manganese superoxide dismutase activity increased in the diaphragm but reduced in the quadriceps relative to shams (P < 0.01). Metabolic enzymes were unaltered in the diaphragm, but cytochrome c oxidase activity (P < 0.01) decreased and lactate dehydrogenase activity (P < 0.05) increased in the quadriceps of CHF animals. Protein expression of the E3 ligase muscle ring finger 1 and proteasome activity were increased (P < 0.05) in both the diaphragm and quadriceps in CHF rats compared with shams.
Chronic heart failure induced divergent antioxidative and metabolic but similar catabolic responses between the diaphragm and quadriceps. Despite the quadriceps demonstrating significant impairments in CHF, apparent beneficial adaptations of an increased antioxidative capacity were induced in the diaphragm. Nevertheless, muscle ring finger 1 and proteasome activity (markers of protein degradation) were elevated and oxidative enzyme activity failed to increase in the diaphragm of CHF rats, which suggest that a myopathy is likely present in respiratory muscle in CHF, despite its constant activation.
慢性心力衰竭（CHF）会导致肢体和呼吸肌无力，这会导致运动耐力下降以及发病率和死亡率增加，但其分子机制仍知之甚少。因此，我们旨在比较CHF动物模型中膈肌和股四头肌的抗氧化能力、能量代谢以及分解代谢/合成代谢平衡参数。
对Wistar Kyoto大鼠进行左冠状动脉前降支结扎（n = 13）或假手术（n = 11）。12周后，进行超声心动图检查和左心室（LV）压力变化最大速率的有创测定。评估股四头肌和膈肌中的抗氧化和代谢酶活性以及分解代谢/合成代谢标志物的表达。
结扎大鼠出现CHF（即严重的左心室扩张、左心室射血分数降低以及左心室压力变化最大速率受损；P < 0.001）。CHF大鼠的膈肌和股四头肌中抗氧化酶的反应不同，与假手术组相比，CHF大鼠膈肌中的谷胱甘肽过氧化物酶和锰超氧化物歧化酶活性增加，而股四头肌中的活性降低（P < 0.01）。膈肌中的代谢酶未改变，但CHF动物股四头肌中的细胞色素c氧化酶活性降低（P < 0.01），乳酸脱氢酶活性增加（P < 0.05）。与假手术组相比，CHF大鼠膈肌和股四头肌中E3连接酶肌肉环形指蛋白1的蛋白表达和蛋白酶体活性均增加（P < 0.05）。
慢性心力衰竭在膈肌和股四头肌之间诱导了不同的抗氧化和代谢反应，但分解代谢反应相似。尽管股四头肌在CHF中表现出明显损伤，但膈肌中诱导了抗氧化能力增加的明显有益适应性变化。然而，CHF大鼠膈肌中肌肉环形指蛋白1和蛋白酶体活性（蛋白质降解标志物）升高，氧化酶活性未能增加，这表明尽管呼吸肌持续激活，但CHF中呼吸肌可能存在肌病。
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