Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle
Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle
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DOI：
10.1002/ejhf.239
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发表时间：
2015-03-01
影响因子：
18.2
通讯作者：
Adams, Volker
中科院分区：
文献类型：
--
作者：
Bowen, T. Scott;Rolim, Natale P. L.;Adams, Volker
目的外周肌肉功能障碍是导致射血分数保留（HFpEF）心力衰竭患者运动不耐受（即呼吸困难和疲劳）的关键机制；然而，潜在的分子和细胞机制仍然未知。因此，我们使用动物模型来阐明 HFpEF 在膈肌和比目鱼肌中引起的潜在分子、线粒体、组织学和功能改变，同时还确定与运动训练相关的可能益处。方法和结果雌性 Dahl 盐敏感大鼠分别喂食 0.3% 或 8% NaCl 的低盐 (CON; n = 10) 或高盐 (HFpEF; n = 11) 饮食，或高盐饮食与跑步机运动训练相结合（n = 11）。与低盐大鼠相比，高盐大鼠出现（P < 0.05）HFpEF。与CON相比，HFpEF大鼠的膈肌表现出（P < 0.05）：纤维类型从快肌纤维向慢肌纤维转变；纤维萎缩；促氧化能力下降但抗氧化能力增强；蛋白酶体激活减少；原位线粒体呼吸受损；以及体外肌肉无力和易疲劳性增加。比目鱼肌还表现出许多改变（P < 0.05），包括纤维萎缩、抗氧化能力降低、线粒体密度降低和易疲劳性增加。然而，运动训练可以预防膈肌和比目鱼肌的线粒体和功能损伤（P < 0.05）。结论我们的研究结果首次证明 HFpEF 会诱导膈肌和比目鱼肌发生显着的分子、线粒体、组织学和功能改变，而运动训练可以减弱这种改变。因此，这些数据揭示了 HFpEF 运动不耐受的新机制和潜在治疗方法。
AimsPeripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training.Methods and resultsFemale Dahl salt-sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low-salt rats, high-salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast-to-slow twitch; fibre atrophy; a decreased pro-oxidative but increased anti-oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti-oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05).ConclusionOur findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.