ETIOLOGY, TIMECOURSE, AND FUNCTIONAL SEQUELAE OF AGE-ASSOCIATED SARCOPENIA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。虽然与年龄相关的肌肉减少症（即骨骼肌质量和收缩能力的丧失）的机制尚不清楚，但众所周知，晚期肌肉减少症会导致功能下降和虚弱表型，从而导致依赖、残疾、住院和死亡的高风险。肌肉减少症的形态学和功能指标在50岁以后出现加速；然而，引发这种衰退的具体病理生理机制尚不清楚。骨骼肌卫星细胞在修复/再生过程中维持肌肉质量方面发挥着必要的作用，我们将验证随着年龄增长而减弱的卫星细胞活性是年龄相关性肌肉减少症的关键调节因子的假设。我们预测，与年龄相关的肌肉质量的进行性减少是由于卫星细胞活性有限导致的不完全修复反复发作的累积结果。我们将评估肌肉生长抑制素作为卫星细胞随年龄抑制的可能介质，我们预测卫星细胞抑制将导致急性负荷发作时肌原性反应减弱。我们期望这是最显著的个体与先进的肌肉减少症的特点是我们的模型的肌肉减少表型。因此，本研究项目的总体目标是表征肌肉减少症的时间过程、其分子触发因素和功能衰退的表型预测。我们的人体实验设计范围广泛，包括体内生理测试、原位免疫组织化学研究、生化研究和原代培养卫星细胞的体外研究。拟议的转化研究项目将首次全面评估肌肉减少症的病因和临床结果，使用跨越成人年龄范围的单个人类受试者队列。总体的假设。我们假设II型肌纤维萎缩和肌纤维损失是肌肉减少表型的特征，部分是由对负荷的肌源性反应减少介导的。我们将评估肌肉生长抑制素作为一个可能的中介钝的肌原性反应。无论实际年龄如何，我们假设这种肌生成抑制在晚期肌肉减少症患者中最为普遍。我们将通过研究3个年龄组来检验30-70岁以上成年人的以下特定假设：年轻（YG， 30-50岁），年轻（YO， 55-65岁）和老年（OL， 70岁以上）成年人。假设1。无论实际年龄如何，我们假设具有共同肌肉减少表型（基于形态学和性能指标）的患者对急性阻力运动负荷的肌原性反应迟钝。我们预测，与非肌肉减少表型相比，运动诱导的肌生成调节因子（myf-6、肌原素、MyoD）、负荷敏感的IGF-I以及细胞周期蛋白B1和Dl的表达（作为卫星细胞激活的指标）将受到阻碍。假设2。我们预测，随着年龄的增长，卫星细胞活性的降低将与肌肉生长抑制素蛋白和基因表达的年龄相关增加有关。肌肉卫星细胞数量的减少将在50岁以上的年龄组中检测到，原位观察到组织切片上卫星细胞频率减少，体外观察到每单位肌肉质量培养的卫星细胞产量降低，种群数量减少，衰老翻倍。在原代培养中，我们预测与年龄相关的基础增殖和分化率降低(即。肌管的形成)。然而，给予适当的有丝分裂刺激（如IGF-I， bFGF），我们期望在所有年龄的个体培养的卫星细胞中出现类似的增殖反应。这些新的数据将为肌少症的研究和未来的临床应用提供急需的基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While the mechanisms of age-associated sarcopenia (i.e. loss of skeletal muscle mass and contractile capacity) are poorly understood, it is well known that advanced saropenia leads to functional decline and to the frailty phenotype which confers high risk for dependence, disability, hospitalization, and mortality. Morphologic and functional indices of sarcopenia appear to accelerate beyond age 50; however, the specific pathophysiology triggering the decline is as yet unclear. Skeletal muscle satellite cells play a requisite role in maintaining muscle mass during repair/regeneration and we will test the hypothesis that blunted satellite cell activity with age is a key modulator of age-related sarcopenia. We predict the progressive age-related decrease in muscle mass is the cumulative result of repeated episodes of incomplete repair consequent to a Limited satellite cell activity. We will evaluate myostatin as a likely mediator of satellite cell suppression with age and we predict satellite cell suppression will lead to a blunted myogenic response to an acute loading bout. We expect this to be most notable among individuals with advanced sarcopenia as characterized by our model of the sarcopenic phenotype. The overall goals of this research project are therefore to characterize the sarcopenia timecourse, its molecular triggers, and the phenotype predictive of functional decline. Our human experimental design runs the gamut as it includes in vivo physiologic testing, immunohistochemical studies in situ, biochemical studies, and in vitro studies of satellite cells in primary culture. The proposed translational research project would provide the first comprehensive assessment of sarcopenia etiology and clinical outcomes using a single cohort of human subjects spanning the adult age range. Overall Hypothesis. We hypothesize the type II myofiber atrophy and loss of myofibers, which are characteristic of the sarcopenic phenotype, are mediated in part by a reduced myogenic response to loading. We will evaluate myostatin as a likely mediator of the blunted myogenic response. Irrespective of chronological age, we hypothesize that this inhibition of myogenesis is most prevalent in individuals with advanced sarcopenia. We will test the following specific hypotheses in adults 30-70+ years of age by studying 3 age groups: Younger (YG, 30-50 yr), Young Old (YO, 55-65 yr), and Older (OL, 70+ yr) adults. Hypothesis 1. Irrespective of chronological age, we hypothesize that patients sharing a common sarcopenic phenotype (based on morphologic and performance indices) will demonstrate a blunted myogenic response to an acute resistance exercise loading bout. We predict exercise-induced expression of the myogenic regulatory factors (myf-6, myogenin, MyoD), load-sensitive IGF-I, and expression of the cyclins B1 and Dl (as indices of satellite cell activation) will be hampered in these patients compared to the non-sarcopenic phenotype. Hypothesis 2. We predict reductions in satellite cell activity with advancing age will be associated with age-related increases in myostatin protein and gene expression. Reductions in the muscle satellite cell population will be detected in age groups beyond age 50 as noted in situ by reduced satellite cell frequency on tissue sections and in vitro by a lower satellite cell yield in culture per unit muscle mass and a reduced number of population doubling to senescence. In primary culture we predict an age-related reduction in the rate of basal proliferation and differentiation (ie. myotube formation). Given appropriate mitogenic stimuli (e.g. IGF-I, bFGF), however, we expect a similar proliferative response in cultured satellite cells from individuals of all ages. These novel data will provide a much needed foundation in sarcopenia research and future clinical applications.