Exploring the role of cathepsins in sarcopenia-related traits: Insights from a Mendelian randomization study

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.