Satellite stem cell biology

描述（由申请人提供）：肌肉减少症患者数量的大量增加，以及由此带来的残疾、痛苦和辅助护理生活费用的负担正在发生。骨骼肌生长衰竭已报道在老年人类和老年动物肥大模型。在后肢固定萎缩后，老年大鼠的骨骼肌在77天内不会再生，而在年轻大鼠中，再生在30天内就完成了。这些事实表明，迫切需要了解在老年人中产生肌肉萎缩和虚弱的细胞机制。本研究的长期目标是更好地了解衰老和缺乏运动过程中肌肉祖细胞增殖和分化的影响因素，这些因素会加速衰老过程中的肌肉萎缩。由于igf - 1可以拯救老年大鼠的肌肉减少症和肌肉再生失败，特异性目标1将把这些观察扩展到细胞机制。Specific Aim 1的一般假设是IGF-I通过细胞核FoxO1水平调节衰老Fischer 344 x Brown Norway大鼠原代肌祖细胞中p27Kip1、Gadd45和MnSOD基因的表达。医学的一个范例是识别负责病理的分子，以改善预防和治疗，这是Specific Aim 1的目标之一。特异性Aim 2将确定p53和Sir2在损害老年动物骨骼肌或年轻和老年动物固定肢体肌肉祖细胞的增殖和成肌潜能方面所起的作用。p53和Sir2的过表达和沉默将分别导致功能的获得和丧失。Specific Aim 3将采用转录谱分析来鉴定卫星细胞、卫星细胞侧群和年轻、成年、老年分化肌管中先前未识别的mRNA差异，以提供新的候选因素，这些因素可以测试导致细胞行为随年龄变化的差异。从已鉴定的mrna中，选择基因进行克隆和功能分析，以确定它们的过表达或沉默是否以与衰老表型一致的方式改变肌肉细胞表型。研究结果将为设计预防和治疗肌肉减少症和身体虚弱的疗法提供更科学的依据。

DESCRIPTION (provided by applicant): A massive increase in the number of humans with sarcopenia, and the resulting burden of their disability, suffering, and the expense of assisted care living is occurring. Skeletal muscle growth failures have been reported in aged humans and hypertrophy models of aged animals. Following atrophy by hindlimb immobilization, skeletal muscle in aged rats does not regrow for 77 days, whereas in young rats regrowth is strikingly complete by 30 days. These facts suggest an urgency to understand cellular mechanisms producing muscle atrophy and weakness in the elderly. The long-term objective of this proposal is to gain a better understanding of factors impairing proliferation and differentiation of muscle progenitor cells during aging and physical inactivity, which accelerates muscle wasting during aging. As IGF-I rescues sarcopenia and the failure of muscle to regrow from immobilization in the old rats, Specific Aim 1 will extend these observations to cellular mechanisms. The general hypothesis of Specific Aim 1 is that IGF-I regulates the expression of p27Kip1, Gadd45, and MnSOD genes through nuclear FoxO1 levels in primary rat muscle progenitor cells of aging Fischer 344 x Brown Norway rats. A paradigm of medicine is to identify molecules responsible for pathologies to improve prevention and cures, which is one goal of Specific Aim 1. Specific Aim 2 will determine the roles that p53 and Sir2 play in impairing the proliferative and myogenic potential of muscle progenitor cells taken from skeletal muscles of old animals or from immobilized limbs of young and old animals. Overexpression and silencing of p53 and Sir2 will be employed to produce gain and loss of function, respectively. Specific Aim 3 will employ transcript profiling to identify previously unidentified mRNA differences in satellite cells, the side population of satellite cells, and differentiating myotubes at young, adult, I and old ages in order to provide novel candidate factors which can be tested for contributing to the differences l in cell behavior with aging. From the identified mRNAs, genes will be selected for cloning and functional l analysis to determine if their overexpression or silencing alters muscle cell phenotype in a manner consistent I with the aging phenotype. The outcomes of the research will provide a more scientific basis to devise therapies to prevent and treat sarcopenia and physical frailty.