Cellular and genomic measures of stem cell function in age-related human muscle atrophy

 描述(申请人提供)：随着年龄的增长，骨骼肌质量和力量的丧失正在成为美国和欧洲最重要的医学问题之一。越来越多地，阿尔茨海默氏症等衰老的关键疾病与肌肉丧失和运动能力丧失有关。与年龄相关的肌肉进行性丧失的细胞和分子基础存在争议。一种假设是，干细胞样卫星细胞的肌源性储备变得枯竭，无法维持肌肉，因为需要替换因日常活动而受损的肌肉。第二，与年龄相关的功能障碍反映了在肌肉纤维的应激环境中，线粒体和核基因组的损害逐渐积累。这两个主要假设并不是相互排斥的。我们建议在人类肌肉中测试这些想法，方法是将不同年龄的身体的肌肉片段移植到免疫缺陷宿主小鼠身上，在那里我们已经证明，卫星干细胞被激活，形成新再生的小肌肉，与人类的肌肉非常相似，是体内再生人类肌肉最真实的模型。如果卫星细胞功能耗尽，随着捐赠者身体年龄的增长，其再生效率和/或效果将会下降。因为再生的肌肉是重新形成的，所以它里面的细胞核和线粒体以前不会暴露在肌肉纤维内的氧化和自由基损伤中，它们的基因组将作为损伤前的标准，用来比较制作移植物的身体肌肉中存在的核和线粒体基因组。如果这种基因组损伤是衰老过程的一个重要部分，我们应该发现随着身体年龄的增加，移植物和身体基因组之间的差异越来越大。因此，我们将检验与年龄相关的人类肌肉功能丧失的两个主要候选假说。这个项目代表了同一实验室中两名经验丰富的研究人员之间的专业知识的综合，这些研究人员具有不同生物学学科的背景，并具有长期成功的合作研究历史。

 DESCRIPTION (provided by applicant): Loss of skeletal muscle mass and strength with increasing age is becoming one of the most important medical issues in the USA and Europe. Increasingly, key morbidities of aging, such as Alzheimer's disease, are associated with loss of muscle and loss of exercise activity. The cellular and molecular basis of age-related progressive loss of muscle is disputed. One hypothesis is that the myogenic reserves of stem-like satellite cells become exhausted and unable to maintain muscle in the face of the need to replace muscle damaged by day- to-day activity. A second is that age-related malfunction reflects the progressive accumulation of damage to the mitochondrial and nuclear genomes within the stressful environment of the muscle fibre. These two main hypotheses are not exclusive of one another. We propose to test these ideas in human muscle by grafting fragments of muscle from cadavers of various ages into immunodeficient host mice where we have shown that the satellite stem cells become activated to form small newly regenerated muscles that closely resemble human muscle in man and are the most authentic model available of a regenerated human muscle in vivo. If the satellite cells become functionally exhausted, it will register as a drop in efficiency and/or effectiveness of regeneration with age of the donor cadaver. Because the regenerated muscle is formed anew, the nuclei and mitochondria within it will not have been previously exposed to the oxidative and free-radical damage within muscle fibres and their genomes will act as a pre- damage standard against which to compare the nuclear and mitochondrial genomes present within the cadaver muscle from which the graft was made. If such genomic damage is a significant part of the aging process, we should detect increasing discrepancies between the graft and cadaver genomes with increasing age of the cadaver. Thus, we will have tested the two main candidate hypotheses of age-related loss of function in human muscle. This project represents a synthesis of expertise between two experienced researchers in the same laboratory with backgrounds in different biological disciplines and with a long history of successful collaborative research.