Impaired Mitochondrial Energetics is a Driver of Hemodialysis Access Related Hand Dysfunction

项目总结 目前，在美国约有425,000名患者接受血液透析(HD)，据估计 这些人中有30%-60%的人在接受血液通路手术后有某种程度的手功能障碍。潜在的 导致这一毁灭性问题的病理生理机制还知之甚少。肾脏 功能障碍(RD)环境导致HD患者的各种生理性紊乱，包括 氧化应激(OS)和慢性炎症已被认为是加速的主要因素 动脉粥样硬化和死亡率上升。OS的深刻变化有助于骨骼肌和神经肌肉 在这一人群中，连接功能障碍与肌肉萎缩和虚弱相关。动静脉瘘手术导致重大 四肢的血流动力学变化，这对骨骼肌和 神经运动终板。由我们以前的工作支持，以及与RD相关的骨骼的初步数据 肌肉线粒体表型改变，我们认为RD驱动的线粒体功能障碍改变骨骼 AVF诱导的肌肉和神经肌肉接头反应导致临床上明显的手 功能障碍。此外，这些路径可以在AVF创建之前或在手的第一个证据时被修改 功能障碍，以逆转/预防功能障碍。我们的假设是RD环境破坏了 线粒体和细胞能量学导致OS升高，使接受AVF手术的患者容易 发生骨骼肌和神经肌肉连接紊乱导致临床上有意义的手 功能障碍。RD介导的线粒体损伤因局部血流动力学改变而进一步加重 通过不良适应的OS代谢反应产生AVF，从而导致临床上 明显的手功能障碍。目标1将确定RD如何影响线粒体和细胞能量学 动静脉瘘诱导的肢体缺血加重。通过一系列的体外实验，我们将揭示 RD影响线粒体能量学导致氧化损伤的生化机制 磷酸化和OS增加。目标2将确定全局或线粒体靶向的疗效 在动静脉动静脉瘘手术前后给予抗氧化剂治疗。使用一种新的RD小鼠AVF模型， 我们将确定是全局(N-乙酰半胱氨酸)还是线粒体靶向(AAV)递送线粒体 靶向过氧化氢酶)抗氧化疗法对动静脉瘘引起的肌肉功能障碍具有治疗潜力。目标3 将评估线粒体健康与动静脉瘘引起的人类手功能障碍之间的关系 病人。线粒体健康状况将使用从RD患者制备的通透性肌纤维进行原位检测 动静脉瘘手术前后：将评估线粒体表型变化及其与 一系列血流动力学、神经生理学和生物力学结果的变化调节频谱 手的功能将被确定。

PROJECT SUMMARY Currently, in the United States, there are ~425,000 patients receiving hemodialysis (HD) and it is estimated that 30-60% of this population have some element of hand dysfunction after hemoaccess surgery. The underlying pathophysiologic mechanisms responsible for this devastating problem are poorly understood. The renal dysfunction (RD) milieu causes a variety of physiologic derangements in HD patients including increased oxidative stress (OS) and chronic inflammation that have been implicated as major contributors to accelerated atherosclerosis and elevated mortality. Profound changes in OS contribute to skeletal muscle and neuromuscular junction dysfunction associated with muscle atrophy and frailty in this population. AVF surgery causes significant hemodynamic changes in the extremity which presents an adaptive challenge to the skeletal muscle and neuromotor end-plate. Supported by our previous work, as well as preliminary data on RD associated skeletal muscle mitochondrial phenotypic changes, we propose that RD driven mitochondrial dysfunction alters skeletal muscle and neuromuscular junction responses to AVF induced ischemia leading to clinically apparent hand dysfunction. Further, these pathways can be modified either prior to AVF creation or at first evidence of hand dysfunction to reverse/prevent the functional impairment. Our hypothesis is that the RD milieu disrupts mitochondrial and cellular energetics resulting in elevated OS predisposing patients undergoing AVF surgery to developing skeletal muscle and neuromuscular junction perturbations causing clinically significant hand dysfunction. RD mediated mitochondrial impairments are further exacerbated by local hemodynamic changes following AVF creation through maladaptive OS metabolic responses that drives the diversity of clinically apparent hand dysfunction. Aim 1 will establish how RD impacts mitochondrial and cellular energetics that are exacerbated by AVF-induced limb ischemia. Using a series of in vitro experiments, we will uncover the biochemical mechanisms by which RD impacts mitochondrial energetics leading to impaired oxidative phosphorylation and increased OS. Aim 2 will determine the efficacy of global or mitochondrial-targeted antioxidant therapies delivered prior to- and following AVF surgery in mice. Using a novel RD murine AVF model, we will determine whether global (N-acetylcysteine) or mitochondrial-targeted (AAV delivery of mitochondrial targeted catalase) antioxidant therapy have therapeutic potential for AVF-induced muscle dysfunction. Aim 3 will evaluate the association between mitochondrial health and AVF-induced hand dysfunction in human patients. Mitochondrial health will be examined in-situ using permeabilized myofibers prepared from RD patients before and after AVF surgery: mitochondrial phenotypic changes will be evaluated and their association with changes in serial hemodynamic, neurophysiological and biomechanical outcomes modulating the spectrum of hand function will be determined.