Integration of CD4+ T cell dynamic expression of quantitative trait loci reveals immunotherapeutic targets for sarcopenia

Abstract

BACKGROUND: Sarcopenia is a degenerative illness in the elderly, and there is currently a dearth of particular therapeutic medications. Abnormalities in immune cells are risk factors for sarcopenia. CD4+ T lymphocytes play a vital role in skeletal muscle repair and regeneration. Previous research generally used expression quantitative trait loci data from whole tissues or blood to identify pharmacological targets, making it difficult to uncover the regulatory effects of gene expression on distinct cell subpopulations and their dynamic activation states. This study integrates dynamic expression quantitative trait locus data of CD4+ T cells to evaluate the immune cell specificity and activation time-dependent impacts of gene expression on sarcopenia, providing a platform for the development of precise immune intervention techniques. OBJECTIVE: To reveal the specific causal relationship between gene expression in different activation phases of CD4+ T cell subpopulations and sarcopenia. METHODS: Based on the dynamic eQTL data of CD4+ T cells from SOSKIC et al. (covering 46 cell-activation states in European populations), the Database of Immune Cell Expression, eQTLs and Epigenomics (DICE), eQTLGen, Genotype-Tissue Expression (GTEx), and GWAS Catalog, a two-sample Mendelian randomization analysis was systematically conducted. First, using CD4+ T cell dynamic eQTLs as exposure and sarcopenia phenotypes as outcomes, candidate genes were screened. Then, eQTL data from immune cells, whole blood, and skeletal muscle tissue were used for validation. Additionally, summary-data-based Mendelian randomization (SMR), heterogeneity tests, colocalization analysis, and differential gene expression analysis (using GEO dataset GSE111016) were performed to verify reliability. All data were publicly available summary statistics and met ethical requirements. All analyses strictly selected instrumental variables and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS AND CONCLUSION: (1) SMR and heterogeneity tests showed that RAB29, NDUFS3, and MMP24OS had specific causal associations with sarcopenia. Specifically, expression of RAB29 in CD4+ naive T cells activated for 5 days and MMP24OS in CD4+ memory T cells activated for 5 days were positively associated with sarcopenia risk, while NDUFS3 expression in naive T cells activated for 16 and 40 hours was negatively associated with sarcopenia risk. (2) Colocalization analysis further confirmed that eQTLs for RAB29, NDUFS3, and MMP24OS shared potential causal variants with sarcopenia GWAS signals. (3) Differential expression analysis showed that NDUFS3 was significantly downregulated in sarcopenia patients compared with healthy controls, while RAB29 and MMP24OS showed no significant difference. NDUFS3 was identified as a potential gene therapy target with temporal regulatory characteristics in CD4+ T cells. This analysis was based on European population data; future studies should introduce dynamic eQTL Mendelian randomization frameworks to develop precise T-cell functional timing intervention strategies for the Chinese population.

1. Introduction

Sarcopenia is a chronic degenerative muscle disease associated with aging (ICD-10: M62.84) [1], characterized by progressive loss of muscle mass and strength. It increases the risk of neurodegenerative diseases [2], osteoarthritis, and diabetes [3-4], and leads to a higher risk of falls due to motor dysfunction [5], severely affecting patients' quality of life. Globally, approximately 50 million people suffer from sarcopenia, and with population aging, the number is expected to exceed 500 million by 2050 [6]. Exercise therapy is considered the first-line strategy for prevention and treatment [7-8]. However, for sarcopenia patients with comorbidities such as osteoarthritis or cognitive impairment, exercise intervention is difficult to implement and adherence is poor [9]. Drug therapy holds great potential when exercise is limited, yet no specific drugs are currently available [10]. Therefore, exploring novel therapeutic targets is urgent.

Target discovery based on disease pathogenesis has become a core strategy in modern drug development and precision medicine. Studies indicate that immune cells regulate the onset and progression of sarcopenia through chronic inflammation, modulation of muscle protein metabolism, and effects on skeletal muscle satellite cell function [11-13]. Among them, CD4+ T cells and their subsets, as core components of the adaptive immune system, play regulatory roles in skeletal muscle injury repair and sarcopenia development [11,14-17]. Changes in the number of CD4+ T cells and their subsets in peripheral blood are closely related to the occurrence and progression of sarcopenia [18-22]. The differentiation process involves metabolic reprogramming, which is crucial for T cell function and muscle homeostasis.