Hou Yiwen, Deng Huaxin, Liu Wei, Liu Yan
School of Public Health, Hengyang Medical School, University of South China, Hengyang, China.
Department of Occupational Health and Radiation Health, Chongqing Center for Disease Control and Prevention, Chongqing, China.
Medicine (Baltimore). 2025 Jun 6;104(23):e42700. doi: 10.1097/MD.0000000000042700.
Sarcopenia, a degenerative loss of skeletal muscle mass, strength, and function, poses a significant public health issue, particularly among aging populations. Cathepsins have recently emerged as key regulators of muscle metabolism and potential contributors to sarcopenia. This study employed Mendelian randomization (MR) to elucidate the causal relationships between 10 specific cathepsins and sarcopenia-related phenotypes, particularly appendicular lean mass (ALM) and handgrip strength, to identify potential therapeutic targets for sarcopenia intervention. A two-sample MR approach was used, employing genetic variants as instrumental variables to explore the impact of cathepsins on ALM and handgrip strength. ALM-related genetic association data were sourced from the UK Biobank, whereas grip strength data were derived from a meta-analysis focused on muscle weakness. Cathepsin levels were obtained using data from the INTERVAL study. The primary analysis method was the inverse variance weighted method, supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses to confirm the robustness of the findings. Positive associations of cathepsin S and E with ALM were demonstrated, whereas negative associations were observed for cathepsin F and B. No significant associations were identified between any cathepsin and grip strength in the primary inverse variance weighted analysis; however, secondary analyses indicated that cathepsin S may serve as a potential risk factor for reduced grip strength. Cathepsins S, E, F, and B were identified as playing significant roles in regulating muscle mass and strength, with cathepsin S potentially affecting grip strength. Targeting these enzymes may offer a viable strategy for developing treatments for sarcopenia. Although causal insights were provided, limitations include reliance on genetic data predominantly from European populations and the use of summary-level data, which constrains generalizability and hinders exploration of individual-level variability and molecular mechanisms. Future studies should validate these findings across diverse populations and investigate the effects of cathepsin on muscle health.
肌肉减少症是骨骼肌质量、力量和功能的退行性丧失，是一个重大的公共卫生问题，在老年人群中尤为突出。组织蛋白酶最近已成为肌肉代谢的关键调节因子，并可能导致肌肉减少症。本研究采用孟德尔随机化（MR）方法，以阐明10种特定组织蛋白酶与肌肉减少症相关表型之间的因果关系，特别是与四肢瘦体重（ALM）和握力的关系，以确定肌肉减少症干预的潜在治疗靶点。采用两样本MR方法，以基因变异作为工具变量，探讨组织蛋白酶对ALM和握力的影响。与ALM相关的基因关联数据来自英国生物银行，而握力数据则来自一项针对肌肉无力的荟萃分析。组织蛋白酶水平通过INTERVAL研究的数据获得。主要分析方法是逆方差加权法，并辅以MR-Egger、简单模式、加权中位数和加权模式分析，以确认研究结果是否稳健。结果表明，组织蛋白酶S和E与ALM呈正相关，而组织蛋白酶F和B与ALM呈负相关。在主要的逆方差加权分析中，未发现任何组织蛋白酶与握力之间存在显著关联；然而，二次分析表明，组织蛋白酶S可能是握力降低的潜在危险因素。组织蛋白酶S、E、F和B被确定在调节肌肉质量和力量方面发挥重要作用，其中组织蛋白酶S可能影响握力。针对这些酶可能为开发肌肉减少症治疗方法提供可行策略。尽管提供了因果关系见解，但局限性包括主要依赖来自欧洲人群的遗传数据以及使用汇总水平数据，这限制了普遍性，并阻碍了对个体水平变异性和分子机制的探索。未来的研究应在不同人群中验证这些发现，并研究组织蛋白酶对肌肉健康的影响。
