Potential regulators and metabolic networks of muscle fatty infiltration: genomic and radiomics investigation based on 33 300 participants

Background: Muscle fatty infiltration (MFI), the pathological replacement of muscle by adipose tissue in chronic diseases, lacks comprehensive genetic characterization despite known cellular contributors. Elucidating its genetic architecture and clinical correlations could reveal therapeutic targets for this debilitating condition. Materials and methods: We performed GWAS on 33,300 participants’ genomic/MRI data, identifying MFI-associated loci. Fine-mapping (GCTA-COJO/FUMA), Mendelian randomization (tissue-specific genes, plasma proteins, metabolites), and genetic correlation (LDSC) analyses were conducted. KLF5’s functional role was validated through inhibition experiments in fibro-adipogenic progenitors (FAPs) and murine immobilization-induced MFI models. Results: GWAS revealed 91 significant SNPs across 26 loci, with risk genes enriched in olfactory transduction and JAK-STAT pathways. Multi-omics integration identified, KLF5 as a key transcriptional regulator, CHRDL2/HLA-E as circulating risk protein and phosphatidylcholines/triglycerides as causal metabolites, and (4) genetic correlations between MFI and metabolic/musculoskeletal disorders. Experimentally, KLF5 suppression reduced adipo-fibrogenic FAP differentiation and improved muscle histology in mice. Conclusion: Our study delineates MFI’s polygenic basis, establishes clinical-metabolic relationships, and mechanistically validates KLF5 as a target. These findings provide a framework for treating MFI through metabolic modulation or KLF5 inhibition, with broader implications for muscle-degenerative comorbidities.