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

 描述（由申请人提供）：随着年龄的增长，骨骼肌质量和力量的损失正在成为美国和欧洲最重要的医学问题之一。越来越多的衰老的关键疾病，如阿尔茨海默病，与肌肉损失和运动活动的损失有关。与年龄相关的肌肉进行性损失的细胞和分子基础是有争议的。一种假设是，干细胞样卫星细胞的生肌储备变得耗尽，并且在需要替换因日常活动而受损的肌肉时无法维持肌肉。第二种是，与年龄相关的功能障碍反映了肌纤维的压力环境中线粒体和核基因组损伤的逐步积累。这两个主要假设并不互相排斥。我们建议通过将来自不同年龄的尸体的肌肉片段移植到免疫缺陷的宿主小鼠中来测试这些想法，我们已经证明卫星干细胞被激活以形成与人类肌肉非常相似的小型新再生肌肉，并且是体内再生人类肌肉的最真实模型。如果卫星细胞变得功能性耗尽，则其将记录为随着供体尸体的年龄再生的效率和/或有效性的下降。因为再生肌肉是重新形成的，所以其中的细胞核和线粒体先前不会暴露于肌肉纤维内的氧化和自由基损伤，并且它们的基因组将充当损伤前标准，对照该标准来比较存在于制成移植物的尸体肌肉内的细胞核和线粒体基因组。如果这种基因组损伤是衰老过程的重要组成部分，我们应该检测到随着尸体年龄的增加，移植物和尸体基因组之间的差异越来越大。因此，我们将测试与年龄相关的人体肌肉功能丧失的两个主要候选假设。该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，他们具有不同生物学科的背景，并具有成功合作研究的悠久历史。

 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.