Identification of Metabolomic Profiles for Sarcopenia Traits in Older Whites and Blacks

肌肉减少症是一种主要的健康问题，其特征是与年龄相关的肌肉质量和功能的丧失 随着老龄化人口的迅速增长，带来了巨大的经济负担。其病因主要是 未知，没有批准的药物可用。迫切需要生物标志物， 了解机制，提高预防，诊断和治疗肌肉减少症。最近 肌肉减少症的发展定义包括低肌肉质量和受损的肌肉功能，强调 在获得一个基本的， 全面了解疾病背后复杂的生物学机制。新兴 代谢组学技术为生物标志物的发现提供了强有力的工具。然而， 代谢组学方法在肌肉减少症研究中的应用相当有限。种族/性别特异性和普遍性 与肌肉减少症相关的代谢物从未被研究过。这项研究的目的是确定新的 与老年白人和黑人中多个关键肌肉减少症相关性状相关的代谢组学标记/谱 使用强大的最先进的液相色谱-质谱法（LC-MS） 代谢组学方法。我们将利用我们正在进行的大型路易斯安那州骨质疏松症研究（LOS）及其 广泛的数据存档，以有效招募和检查800名老年白色和黑人受试者（≥ 60岁和200 每个种族性别组的受试者）。与肌肉萎缩症相关的特征，包括肌肉质量、力量和功能， 使用非标准瘦体重/身体质量指数比（ALM/BMI）、握力和通常的 步态速度，分别。以LOS为基础，我们将招募300名受试者作为发现集， 作为验证集。我们将选择100名LOS受试者，其中100名患有高风险和低风险的肌肉减少症， ALM/BMI和手握力值在参与者中分布的下半部分或上半部分 在LOS档案中，作为测试集。在第4年，我们将对第1年注册的100名参与者进行随访，作为 预测集具体目标是：1）鉴定与肌肉减少症特征相关的新型代谢物 （包括种族，性别和性状特异性/共享的）使用非靶向代谢组学方法， 2）使用相同的方法验证目标1中鉴定的性状相关代谢物， 验证集中的非靶向方法，使用已建立的 工作流程，并开发具有绝对定量的靶向LC-MS测定法，以进一步验证 发现和验证集;以及3）评估验证的代谢物在区分受试者中的能力 在测试集中，将高风险与低风险的肌肉减少症患者区分开来，并检查他们对 预测集中肌肉减少症相关性状的纵向变化。凭借创新和最先进的 分析策略，该项目将及时和具有成本效益的提供新的代谢标志物重要， 肌肉减少症的风险，并阐明其生物学机制。

Sarcopenia, characterized by the age-related loss of muscle mass and function, is a major health problem incurring a huge economic burden with the rapid growth of the aging older population. Its etiology is largely unknown, and no approved medication is available. There is an urgent need for biomarkers aimed at understanding the mechanisms and improving the prevention, diagnosis, and treatment of sarcopenia. Recently developed definitions of sarcopenia include both low muscle mass and impaired muscle function, highlighting the necessity of considering different physiological components of sarcopenia in obtaining a fundamental and comprehensive understanding of the complex biological mechanisms underlying the disorder. The emerging metabolomics technology provides a powerful tool for biomarker discovery. However, applications of the metabolomics approach in sarcopenia research are rather limited. The race/sex specificity and generality of sarcopenia-related metabolites have never been investigated. The Goal of the proposed study is to identify novel metabolomic markers/profiles associated with multiple key sarcopenia-related traits in older whites and blacks of both sexes using a powerful state-of-the-art liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approach. We will leverage our large ongoing Louisiana Osteoporosis Study (LOS) and its extensive data archive to efficiently recruit and examine 800 older white and black subjects (≥ 60 years and 200 subjects for each race-sex-group). Sarcopenia-related traits including muscle mass, strength, and function will be measured using the appendicular lean mass/body mass index ratio (ALM/BMI), hand grip strength, and usual gait speed, respectively. Anchored on the LOS, we will enroll 300 subjects as the discovery set and another 300 as the validation set. We will select 100 LOS subjects with high and 100 with low risk for sarcopenia, defined by both ALM/BMI and hand grip strength values in the lower or upper half of the distributions among the participants in the LOS archive, as the testing set. At year 4, we will follow up 100 participants enrolled at year 1 as the prediction set. The Specific Aims are to: 1) identify novel metabolites associated with sarcopenia traits (including race-, sex- and trait-specific/shared ones) using an untargeted metabolomics approach with relative quantification in the discovery set; 2) validate the trait-related metabolites identified in Aim 1 using the same untargeted method in the validation set, elucidate/confirm the identities of metabolites using an established workflow, and develop a targeted LC-MS assay with absolute quantification for further validation in both the discovery and validation sets; and 3) assess the power of the validated metabolites in discriminating subjects with high risk from those with low risk for sarcopenia in the testing set and examine their predictive values for longitudinal changes in sarcopenia-related traits in the prediction set. With the innovative and state-of-the-art analysis strategy, this project will be timely and cost-efficient to provide novel metabolic markers important to sarcopenia risk, and shed lights into its biological mechanisms.