Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Molecular Biology, Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Cardiovasc Res. 2021 Feb 22;117(3):805-819. doi: 10.1093/cvr/cvaa127.
Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischaemic tissue. Here, we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production.
Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analysed. XO-derived ROS production was significantly increased in MI mice from Days 1 to 3 post-surgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham + vehicle (Sham + Veh), MI + vehicle (MI + Veh), and MI + febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI + Feb). Febuxostat or vehicle was administered at 1 and 24 h before surgery, and once-daily on Days 1-7 post-surgery. On Day 28 post-surgery, exercise capacity and mitochondrial respiration in skeletal muscle fibres were significantly decreased in MI + Veh compared with Sham + Veh mice. An increase in damaged mitochondria in MI + Veh compared with Sham + Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibres (higher XO-derived ROS) was reduced via the down-regulation of protein synthesis-associated mTOR-p70S6K signalling in MI + Veh compared with Sham + Veh mice. These impairments were ameliorated in MI + Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function.
XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF.
心力衰竭（HF）患者的运动不耐受部分归因于骨骼肌异常。我们已经表明，活性氧（ROS）在骨骼肌异常中起关键作用，但发病机制尚不清楚。黄嘌呤氧化酶（XO）据报道是缺血组织中 ROS 过度产生的重要介质。在这里，我们测试了假设，即 HF 中的骨骼肌异常最初是由 XO 衍生的 ROS 引起的，并可以通过抑制其产生来预防。
在雄性 C57BL/6J 小鼠中诱导心肌梗死（MI），最终导致 HF，并对对照组小鼠进行假手术。首先分析了 MI 后小鼠骨骼肌中 XO 衍生的 ROS 产生的时间过程。MI 小鼠手术后 1 至 3 天（急性期）中 XO 衍生的 ROS 产生显着增加，而 MI 和假手术组之间在第 7 至 28 天（慢性期）没有差异。其次，将小鼠分为三组：假手术+载体（Sham+Veh），MI+载体（MI+Veh）和 MI+非布司他（XO 抑制剂，5mg/kg 体重/天; MI+Feb）。Febuxostat 或载体在手术前 1 小时和 24 小时给药，并在手术后第 1 至 7 天每天给药一次。手术后第 28 天，与 Sham+Veh 小鼠相比，MI+Veh 小鼠的运动能力和骨骼肌纤维中的线粒体呼吸显着降低。与 Sham+Veh 小鼠相比，MI+Veh 小鼠中受损线粒体的增加也观察到。通过下调与蛋白质合成相关的 mTOR-p70S6K 信号转导，MI+Veh 小鼠中慢肌纤维（较高的 XO 衍生的 ROS）的湿重和横截面积降低。与减少 XO 衍生的 ROS 产生相关，MI+Feb 小鼠中的这些损伤得到改善，而不影响心脏功能。
MI 后急性期的 XO 抑制可预防 HF 小鼠的骨骼肌异常和运动不耐受。
