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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 虽然与年龄相关的骨质疏松症(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，严重的肌质疏松症会导致功能衰退和虚弱的表型，从而导致依赖、残疾、住院和死亡的高风险。骨质疏松症的形态和功能指标 似乎在50岁以后加速；然而，触发下降的具体病理生理学尚不清楚。骨骼肌卫星细胞在修复/再生期间维持肌肉质量起着必要的作用，我们将测试 随着年龄增长，卫星细胞活动减弱的假说是年龄相关性骨质疏松症的关键调节因素。我们预测 随着年龄的增长，肌肉质量逐渐减少，这是由于卫星细胞活动受限导致反复出现不完全修复的累积结果。我们将评估随着年龄的增长，肌肉抑制素可能是卫星细胞抑制的媒介，我们预测卫星细胞抑制将导致对急性负荷比赛的迟钝的生肌反应。我们预计这在晚期石棺减少的患者中最为明显，因为我们的石棺生成表型模型的特征是这种情况。因此，这项研究项目的总体目标是描述骨质疏松症的时间过程、其分子触发因素以及功能衰退的表型预测。我们的人体实验设计包括体内生理测试、原位免疫组织化学研究、生化研究和卫星细胞原代培养的体外研究。拟议的转化性研究项目将首次对石棺减少症的病因和临床结果进行全面评估，使用的是跨越成年年龄范围的单一人类受试者队列。总体假设。我们假设II型肌纤维萎缩和肌纤维丢失，这是肌生性表型的特征，部分是由于对负荷的肌源性反应减少所致。我们将评估肌肉抑制素作为钝化肌源性反应的一个可能的介体。不管实际年龄如何，我们假设这种对肌肉生成的抑制在晚期石棺减少的个体中最为普遍。我们将通过研究3个年龄组在30-70岁以上的成年人中检验以下特定假设：年轻人(YG，30-50岁)、青年老年人(YO，55-65岁)和老年(OL，70+岁)成年人。 假设1：不论年龄大小，我们假设具有共同的骨化表型(基于形态和表现指数)的患者会对急性阻力运动负荷比赛表现出迟钝的生肌反应。我们预测，在这些患者中，运动诱导的生肌调节因子(Myf-6、Mygenin、MyoD)、负荷敏感型IGF-I的表达以及细胞周期蛋白B1和DL(作为卫星细胞激活的指标)的表达将比非骨钙素表型受到阻碍。 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与年龄相关的肌肉生长抑素蛋白和基因表达的增加有关。在超过50岁的年龄组中，肌肉卫星细胞数量的减少将被检测到，正如在组织切片和体外培养中卫星细胞频率的减少和单位肌肉质量培养中卫星细胞产量的降低以及加倍衰老的种群数量的减少所指出的那样。在原代培养中，我们预测基础增殖和分化率随着年龄的增长而降低(即。肌管形成)。然而，如果给予适当的有丝分裂刺激(如IGF-I、bFGF)，我们预计所有年龄段的人在培养的卫星细胞中都会有类似的增殖反应。这些新的数据将为骨质疏松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.