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

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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.