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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。虽然年龄相关性肌肉减少症（即骨骼肌质量和收缩能力的损失）的机制知之甚少，但众所周知，晚期肌肉减少症导致功能下降和虚弱表型，这赋予依赖性、残疾、住院和死亡的高风险。骨骼肌减少症的形态和功能指标似乎在50岁以后加速下降;然而，触发这种下降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，我们将测试以下假设：随着年龄的增长，卫星细胞活性减弱是年龄相关性肌肉减少症的关键调节因子。我们预测，与年龄相关的肌肉质量的进行性减少是由于有限的卫星细胞活性导致的不完全修复的反复发作的累积结果。我们将评估肌生长抑制素作为随年龄增长的卫星细胞抑制的可能介质，我们预测卫星细胞抑制将导致对急性负荷回合的肌源性反应减弱。我们预计这在患有晚期肌肉减少症的个体中最为显著，其特征在于我们的肌肉减少症表型模型。因此，本研究项目的总体目标是描述肌肉减少症的时间进程、其分子触发因素和预测功能下降的表型。我们的人体实验设计涵盖了所有领域，因为它包括体内生理测试、原位免疫组织化学研究、生化研究和原代培养中卫星细胞的体外研究。拟议的转化研究项目将使用跨越成人年龄范围的单个人类受试者队列首次全面评估肌肉减少症病因和临床结局。整体假设。我们假设II型肌纤维萎缩和肌纤维损失，这是肌肉减少表型的特征，部分介导的肌源性反应减少负荷。我们将评估肌生长抑制素作为钝性肌源性反应的可能介质。无论实际年龄，我们假设这种抑制肌生成是最普遍的个体与先进的肌肉减少症。我们将通过研究3个年龄组在30-70岁以上的成年人中测试以下特定假设：年轻人（YG，30-50岁），年轻老年人（YO，55-65岁）和老年人（OL，70岁以上）。假设1.不考虑实际年龄，我们假设患者共享一个共同的肌肉减少表型（基于形态和性能指标）将表现出钝肌源性反应，急性阻力运动负荷回合。我们预测运动诱导的肌源性调节因子（myf-6，肌细胞生成素，MyoD），负荷敏感性IGF-I的表达，以及细胞周期蛋白B1和D1的表达（作为卫星细胞活化的指标）将在这些患者相比，非肌肉减少表型受到阻碍。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年龄相关的肌生长抑制素蛋白和基因表达的增加有关。在超过50岁的年龄组中将检测到肌肉卫星细胞群体的减少，如通过组织切片上卫星细胞频率的减少原位观察到的，以及通过每单位肌肉质量培养物中卫星细胞产量的降低和群体倍增至衰老的数量的减少体外观察到的。在原代培养中，我们预测了与年龄相关的基础增殖和分化速率的降低（即，肌管形成）。然而，给予适当的促有丝分裂刺激（如IGF-I，bFGF），我们预计在培养的卫星细胞从所有年龄段的个人类似的增殖反应。这些新的数据将为肌肉减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.