Mitochondrial Permeability Transitionin Aging Muscle

项目摘要/摘要 线粒体通透性转换(MPT)涉及在线粒体上形成一个非特异性的孔 允许促凋亡蛋白通过的内膜，并引起大量的活性氧爆发 种(ROS)。而MPT在缺血再灌注损伤、心脏衰老、肌肉等方面的病理作用 营养不良和神经退行性变是公认的，MPT在骨骼肌老化中的作用尚未得到证实 解决了。我们在人和啮齿动物肌肉细胞培养中的初步数据表明，MPT是一种新的 肌肉萎缩可以通过干扰调节MPT的蛋白质、击倒caspase 3或 通过猝灭线粒体的ROS。此外，我们还发现线粒体具有较低的诱导阈值。 MPT在衰老的肌肉中的出现，在衰老的人类骨骼肌中MPT的出现增加，并且它 只发生在随着年龄增长而萎缩的肌肉中，最后，我们还表明，在衰老的肌肉中，肌肉纤维与 与正常肌肉纤维相比，接受MPT的线粒体严重萎缩，并表现出 这些特征表明他们已经丧失了神经。在此基础上，本项目的第一个目标是解决根本问题 使用细胞培养模型将MPT与肌肉萎缩联系起来的机制。其次，使用大鼠模型，我们将 调节MPT的钙离子阈值以检验MPT对生成衰老肌肉的必要性和充分性 表型。最后，我们将利用强大的临床数据集、深部肌肉表型分析和 肌肉组织学阻碍了将对875名老年男性进行研究的肌肉运动与衰老研究(Somma 和女性(70岁)，以建立MPT与老年人重要临床结局的翻译相关性 人类。通过这样做，我们的研究将为判断发展小说的价值奠定必要的基础 防止线粒体对MPT敏感的治疗方法作为保存肌肉质量的一种手段 以及老年时的机动性。

Project Summary/Abstract Mitochondrial permeability transition (MPT) involves the formation of a non-specific pore across the mitochondrial inner membrane that allows the passage of pro-apoptotic proteins and induces a large burst in reactive oxygen species (ROS). Whilst the pathological role of MPT in ischemia-reperfusion injury, cardiac aging, muscular dystrophy and neurodegeneration is well-established, the role of MPT in aging skeletal muscle has not been resolved. Our preliminary data in human and rodent muscle cell cultures identify MPT as a novel mechanism of muscle atrophy that can be blocked by interfering with proteins that regulate MPT, knocking down caspase 3, or by quenching mitochondrial ROS. Furthermore, we show that mitochondria have a lower threshold for inducing MPT in aging muscle, that there is an increased occurrence of MPT in aging human skeletal muscle, and that it only occurs in muscles that atrophy with aging, Finally, we also show in aged muscles that muscle fibers with mitochondria undergoing MPT are severely atrophied relative to normal muscle fibers and that they exhibit features suggesting they are denervated. On this basis, the first goal of this project is to address the fundamental mechanisms linking MPT to muscle atrophy using cell culture models. Secondly, using rat models we will manipulate the Ca2+ threshold for MPT to test the necessity and sufficiency of MPT for generating aging muscle phenotypes. Finally, we will leverage the powerful clinical dataset, deep muscle phenotyping, and availability of muscle histology blocks from the Study of Muscle Mobility and Aging (SOMMA) that will study 875 elderly men and women (³70 y), to establish the translational relevance of MPT for important clinical outcomes in elderly humans. By doing so, our studies will lay the foundation necessary to judge the merits of developing novel therapeutic approaches to prevent sensitization of mitochondria to MPT as a means of preserving muscle mass and mobility in advanced age.