BACKGROUND The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA-1 expression and downstream-associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. METHODS Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II-III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. RESULTS Thirty-three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA-1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = -15 ± 0.03%), and tended to increase the p-AKTser473 /AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = -40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross-sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA-1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). CONCLUSIONS AET upregulates microRNA-1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K-AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA-1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross-sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA-1 and in the downstream-associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395).

中文翻译：

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有氧和吸气训练对心力衰竭患者骨骼肌microRNA-1和下游相关通路的影响。

背景技术具有降低的射血分数（HFrEF）的慢性心力衰竭的运动耐受性主要归因于骨骼肌的改变。但是，HFrEF患者骨骼肌病的潜在机制尚未完全了解。我们假设（i）有氧运动训练（AET）和吸气肌肉训练（IMT）会改变HFrEF患者的骨骼肌microRNA-1表达及下游相关途径，（ii）AET和IMT会增加腿部血流量（LBF ），这些患者的功能能力和生活质量。方法将年龄在35至70岁，左心室射血分数（LVEF）≤40％，纽约心脏协会功能分类II-III的患者随机分为对照组，IMT和AET组。通过股外侧肌活检检查骨骼肌变化。通过静脉闭塞体积描记法测量LBF，通过心肺运动试验测量功能能力，并通过明尼苏达州心衰患者问卷调查生活质量。在基线和4个月后对所有患者进行评估。结果33例患者完成了研究方案：对照组（n = 10； LVEF = 25±1％；六名男性），IMT（n = 11； LVEF = 31±2％；三名男性）和AET（n = 12） ； LVEF = 26±2％； 7个男性）。AET而非IMT增加了microRNA-1的表达（P = 0.02;百分比变化= 53±17％），降低了PTEN的表达（P = 0.003;百分比变化= -15±0.03％），并且倾向于增加p-AKTser473 / AKT比（P = 0.06）。此外，AET降低了HDAC4的表达（P = 0.03；变化百分比= -40±19％），而上调的卵泡抑素（P = 0.01；变化百分比= 174±58％），MEF2C（P = 0.05； P = 0.05）。百分比变化= 34±15％）和MyoD表达（P = 0.05；百分比变化= 47±18％）。AET也增加了肌肉的横截面积（P = 0.01）。AET和IMT增加了LBF，功能能力和生活质量。进一步的分析显示，microRNA-1的变化百分比与卵泡抑素mRNA的变化百分比之间具有显着相关性（P = 0.001，rho = 0.58），卵泡抑素mRNA的变化百分比与峰值VO2的变化百分比之间具有显着相关性（P = 0.004，rho = 0.51） 。结论AET上调microRNA-1水平并降低PTEN的蛋白表达，从而降低了对PI3K-AKT通路的抑制作用，该通路调节骨骼肌的向性。microRNA-1水平的增加也降低了HDAC4，MEF2c，MyoD和卵泡抑素的表达也增加了，从而改善了骨骼肌的再生。这些与肌肉横截面积和LBF增大相关的变化有助于骨骼肌病的减轻，并改善HFrEF患者的功能能力和生活质量。IMT不会引起microRNA-1和下游相关途径的变化。IMT引起的功能增强似乎与呼吸功能的改善而不是骨骼肌的变化有关。ClinicalTrials.gov（标识符：NCT01747395）。IMT引起的功能增强似乎与呼吸功能的改善而不是骨骼肌的变化有关。ClinicalTrials.gov（标识符：NCT01747395）。IMT引起的功能增强似乎与呼吸功能的改善而不是骨骼肌的变化有关。ClinicalTrials.gov（标识符：NCT01747395）。