Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese-HFpEF.
Abnormal skeletal muscle blood flow, contractile mechanics and fibre morphology in a rat model of obese-HFpEF.
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DOI：
10.1113/jp280899
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Bowen TS
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文献类型：
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作者：
Espino-Gonzalez E;Tickle PG;Benson AP;Kissane RWP;Askew GN;Egginton S;Bowen TS
心力衰竭的特征是肢体和呼吸肌损伤，限制了功能能力和生活质量。然而，与射血分数降低的心力衰竭（HFrEF）相比，射血分数保留的心力衰竭（HFpEF）引起的骨骼肌改变仍缺乏研究。在这里，我们报告了肥胖-HFpEF诱导大鼠后肢的多种骨骼肌改变，包括与缩短速度相关的肌肉力学受损、纤维萎缩、毛细血管损失和对收缩的血流反应受损，这意味着灌注氧输送限制。我们还证明，肥胖-HFpEF的特征是与去神经支配引起的类似的神经改变-IIb/IIx型（快/糖酵解）纤维萎缩和I型（慢/氧化）纤维肥大。这些发现扩展了HFpEF骨骼肌生理学的现有知识，潜在的运动不耐受，这可能有助于未来的治疗方法。射血分数保留性心力衰竭（HFpEF）诱导的外周骨骼肌和血管改变仍难以确定，治疗靶点有限。本研究使用心脏代谢性肥胖-HFpEF大鼠模型来综合表型骨骼肌力学、血流、微血管和纤维萎缩。比较了瘦型（n = 8）和肥胖型-HFpEF（n = 8）HFRF 1大鼠。评估骨骼肌（比目鱼肌和膈肌）的体外收缩性（等长和等张特性）以及纤维型横截面积、肌球蛋白亚型和毛细血管指数，并估计肌肉PO 2。在原位趾长伸肌（EDL）的收缩力和股动脉血流量进行了评估。HFpEF比目鱼肌显示绝对最大力降低22%，纤维萎缩24%，纤维类型从I型转变为IIa型，毛细血管-纤维比降低17%，尽管毛细血管密度增加（均P < 0.05），保留肌肉PO 2（P = 0.115）和等长比力（P > 0.05）。比目鱼肌等张特性（缩短速度和功率）分别受损高达17%和22%（P < 0.05），而运动充血的幅度减弱了73%（P = 0.012），与肌肉疲劳增加26%（P = 0.079）一致。膈肌改变（P < 0.05）包括IIx型纤维萎缩，尽管I/IIa型纤维肥大，毛细血管指数增加，同时在等长、等张和周期性收缩期间保持收缩特性。总之，肥胖-HFpEF大鼠在收缩过程中表现出骨骼肌血流量变钝，与运动肌肉中的微血管结构重塑、纤维萎缩和等张收缩功能障碍平行。相比之下，隔膜表型保持良好。这项研究发现了许多可能加剧肥胖-HFpEF运动不耐受的肌肉特异性损伤。心力衰竭的特征是肢体和呼吸肌损伤，限制了功能能力和生活质量。然而，与射血分数降低的心力衰竭（HFrEF）相比，射血分数保留的心力衰竭（HFpEF）引起的骨骼肌改变仍缺乏研究。在这里，我们报告了肥胖-HFpEF诱导大鼠后肢的多种骨骼肌改变，包括与缩短速度相关的肌肉力学受损、纤维萎缩、毛细血管损失和对收缩的血流反应受损，这意味着灌注氧输送限制。我们还证明，肥胖-HFpEF的特征是与去神经支配引起的类似的神经改变-IIb/IIx型（快/糖酵解）纤维萎缩和I型（慢/氧化）纤维肥大。这些发现扩展了HFpEF骨骼肌生理学的当前知识，可能是运动不耐受的基础，这可能有助于未来的治疗方法。
Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. Here we report that obese‐HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. We also demonstrate that obese‐HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation – atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches. Peripheral skeletal muscle and vascular alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly identified, with limited therapeutic targets. This study used a cardiometabolic obese‐HFpEF rat model to comprehensively phenotype skeletal muscle mechanics, blood flow, microvasculature and fibre atrophy. Lean (n = 8) and obese‐HFpEF (n = 8) ZSF1 rats were compared. Skeletal muscles (soleus and diaphragm) were assessed for in vitro contractility (isometric and isotonic properties) alongside indices of fibre‐type cross‐sectional area, myosin isoform, and capillarity, and estimated muscle PO2. In situ extensor digitorum longus (EDL) contractility and femoral blood flow were assessed. HFpEF soleus demonstrated lower absolute maximal force by 22%, fibre atrophy by 24%, a fibre‐type shift from I to IIa, and a 17% lower capillary‐to‐fibre ratio despite increased capillary density (all P < 0.05) with preserved muscle PO2 (P = 0.115) and isometric specific force (P > 0.05). Soleus isotonic properties (shortening velocity and power) were impaired by up to 17 and 22%, respectively (P < 0.05), while the magnitude of the exercise hyperaemia was attenuated by 73% (P = 0.012) in line with higher muscle fatigue by 26% (P = 0.079). Diaphragm alterations (P < 0.05) included Type IIx fibre atrophy despite Type I/IIa fibre hypertrophy, with increased indices of capillarity alongside preserved contractile properties during isometric, isotonic, and cyclical contractions. In conclusion, obese‐HFpEF rats demonstrated blunted skeletal muscle blood flow during contractions in parallel to microvascular structural remodelling, fibre atrophy, and isotonic contractile dysfunction in the locomotor muscles. In contrast, diaphragm phenotype remained well preserved. This study identifies numerous muscle‐specific impairments that could exacerbate exercise intolerance in obese‐HFpEF. Heart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. Here we report that obese‐HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. We also demonstrate that obese‐HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation – atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches.