Electrical stimulation reverses the effect of age on skeletal muscle regeneration

摘要：骨骼肌创伤后延迟的和不完全的愈合反应，如手术 或损伤，是在老年人中观察到的常见临床现象。这样的再生赤字是 通常是纤维化形成增加，肌肉间脂肪沉积增加，减少 肌纤维再生，随之而来的收缩能力下降。肝纤维化和脂肪形成增加 继发性损伤归因于老年人从肌源性到纤维化和成脂性转化的增加 肌肉前体细胞(MPC)。幸运的是，与年龄相关的骨骼肌再生能力下降是 潜在可逆的，正如在异时配对(其中循环系统 小动物和老年动物的联合)、基因治疗和动物的直接生长因子注射。 例如，由运动或电刺激(E-STIM)启动的机械传导通路也 促进MPC活化和增殖，有利于肌原纤维的生成。在这项研究中，我们将调查是否 E-stim可以无创地调节肌肉宏观和微观环境以增强骨骼肌 在年老的动物身上治愈。这些研究的具体目的是：1.体外测定E-STIM的能力 在体内，恢复从老年骨骼中分离的肌肉祖细胞(MPC)的再生能力 2.测定体内E-stim促进衰老骨骼肌再生的能力。 在急性肌肉损伤后，通过组织学和功能测试进行分析。的工作假说 这一建议是，应用有针对性的和特定的E-STIM方案可以改善对 衰老动物模型在全组织、细胞和信号水平的损伤。 在我的科学传记中，我一直致力于研究细胞和康复- 改善骨骼肌生理和功能的基础疗法。我打算用美国国立卫生研究院 职业发展奖，以支持我的调查，利用康复原则扭转 年龄对骨骼肌功能的影响。我和我的导师们设计了一份职业发展计划 实现四个具体目标：1)增进对以下领域现状的了解 从分子角度看衰老，2)熟练掌握评估骨骼的分子方法 肌肉和组织的老化，3)提高我的手腕技能，4)保持我对 在负责任的研究行为方面的培训。

ABSTRACT: A delayed and incomplete healing response following skeletal muscle trauma, such as surgery or injury, is a common clinical phenomena observed in elderly individuals. Such a regenerative deficit is typically a result of increased fibrosis formation, increased intermuscular adipose deposition, decreased myofiber regeneration, and subsequent decreased contractility. The increased fibrosis and adipose formation following injury has been attributed to an increased myogenic-to-fibrogenic and -adipogenic conversion of aged muscle precursor cells (MPCs). Fortunately, age-related declines in skeletal muscle regenerative capacity are potentially reversible, as has been observed following heterochronic pairings (in which the circulatory systems of a young and old animal are joined), gene therapy, and direct growth factor injection in animals. Mechanotransductive pathways, initiated by exercise or electrical stimulation (E-stim) for example, also increase MPC activation and proliferation, and favor myogenesis. In this study, we will investigate whether the muscle macro- and micro-environment can be non-invasively modulated by E-stim to enhance skeletal muscle healing in aged animals. The specific aims of these studies are: 1. to determine the ability of E-stim, in vitro and in vivo, to restore the regenerative potential of muscle progenitor cells (MPCs) isolated from aged skeletal muscle and 2. to determine the ability of in vivo E-stim to enhance regeneration of aged skeletal muscle following an acute muscle injury, as analyzed using histology and functional testing. The working hypothesis of this proposal is that application of targeted and specific E-stim protocols can improve the healing response to injury in aged animal models at the whole tissue, cellular and signaling levels. Throughout my scientific biography, I have been committed to a career investigating cellular and rehabilitation- based therapies for the improvement of skeletal muscle physiology and functioning. I plan to use the NIH Career Development Award to support my investigations that utilize rehabilitation principles to reverse the effect of age on skeletal muscle function. My mentors and I have designed a career development plan for the accomplishment of four specific goals: 1) To gain an increased understanding of current state of the field of aging from a molecular stand-point, 2) To become skilled in molecular approaches for assessing skeletal muscle and organismal aging, 3) to improve my grantsmanship skills, and 4) to maintain my commitment to training in the responsible conduct of research.