Cross-organ crosstalk in brain-aging-related sarcopenia: Caudate iron accumulation impairs muscle health via...

Brain aging and sarcopenia represent multisystem manifestations of aging. Although emerging research supports the brain-muscle axis, the causal evidence and mechanisms remain unclear.

Multi-stage genetic analysis investigated cross-organ regulation between brain Quantitative susceptibility mapping(QSM) and muscle health, with replication at each stage. High-Definition Likelihood inference(HDL) and Mendelian randomization(MR) assessed associations between regional QSM and lean body mass(LBM). Single-cell disease relevance score(scDRS) nominated cell types involved in brain-muscle crosstalk. Transcriptome-wide association studies(TWAS) prioritized candidate genes at the tissue level. Candidate genes were replicated at the cellular level through SMR analysis and colocalization, and then exploratorily characterized by simulated knockout. Based on 669 blood-brain barrier(BBB)-related biomarkers, mediation analysis explored mechanisms linking caudate QSM to LBM.

Increased caudate QSM was associated with lower LBM. Caudate vascular cells were involved in the brain-muscle crosstalk. CYBRD1 in the caudate nucleus was associated with LBM across different TWAS methods. SMR and colocalization indicated that CYBRD1 expression in pericytes was positively associated with LBM, grip strength, and physical function. After simulated knockout of CYBRD1, the perturbed genes were enriched in BBB function and structure pathways. Elevated right caudate QSM was associated with decreased plasma TYRO3 levels, which partially mediated the negative effect of right caudate QSM on LBM.

Elevated caudate QSM was associated with muscle atrophy, partly mediated by BBB dysfunction. This brain-muscle axis suggests brain iron management and BBB homeostasis as potential intervention directions for brain aging-related sarcopenia.