Multi-omics and machine learning reveal a critical mediator of PRKCA in quercetin-mediated protection against Sarcopenia.

BACKGROUND

Sarcopenia, the age-associated loss of skeletal muscle mass and function, poses a growing public health challenge. Although dietary flavonoids have been proposed as protective agents due to their antioxidant and anti-inflammatory properties, their precise roles in sarcopenia prevention remain unclear.

METHODS

We integrated data from the National Health and Nutrition Examination Survey (NHANES, 2017-2018) and the Food and Nutrient Database for Dietary Studies (FNDDS) to examine the relationship between flavonoid intake and sarcopenia risk. Using machine learning, LASSO, CatBoost, and SHAP interpretation, we identified key predictive variables. Drug-target genes were retrieved from Drug-Gene Interaction Database (DGIdb), followed by Mendelian randomization using GWAS and QTL summary data. Bulk RNA-seq and single-cell RNA-seq were analyzed to explore molecular pathways. Experimental validation was performed using C2C12 myoblast differentiation assays.

RESULTS

After propensity score matching, BMI, gender, and PIR remained significantly associated with sarcopenia. Machine learning identified flavonoids, particularly quercetin, as key predictors. SHAP values revealed an inverse, dose-dependent association between quercetin intake and sarcopenia predictions in the model. SMR analysis linked quercetin to genes such as PRKCA. Bulk RNA-seq enrichment analysis revealed enrichment of protein kinase C (PKC)-related signaling and downstream MAPK/ERK pathways after quercetin treatment, while scRNA-seq data identified Prkca as a quercetin-responsive gene in muscle fiber populations. Experimental results confirmed that quercetin promotes myoblast differentiation via PRKCA upregulation, accompanied by enhanced ERK1/2 phosphorylation, an effect abolished by the PRKCA inhibitor Go6976.

CONCLUSIONS

Our integrative multi-omics and experimental approach reveals that quercetin is associated with sarcopenia and influence muscle differentiation through PRKCA-ERK signaling. These findings support the potential of flavonoids as targeted dietary interventions for age-related muscle decline.