Atrazine exposure induces skeletal muscle atrophy: Multi-omics insights into mechanisms and therapeutic targets
Year: 2025
Type: article
Abstract: Atrazine (ATZ), a frequently used herbicide, has well-documented toxicities in various organisms, yet its specific impact on skeletal muscle remains largely uncharted. Here, we found that ATZ inhibited myotube formation in C2C12 myoblasts and decreased both body weight and the cross-sectional areas of type IIA, IIB, and IIX myofibers in mice. Furthermore, ATZ drove muscle fiber shifting from mixed oxidative/glycolytic type IIA to fast-glycolytic type IIB, reduced satellite stem cell abundance, and contributed to excessive lipid accumulation. Mechanistically, transcriptomic analyses indicated that ATZ triggered inflammation, oxidative stress, adipogenesis, and protein degradation, as evidenced by elevated ROS, augmented NF-κB pathway, and disrupted protein homeostasis. By integrating transcriptomic data with eQTL and grip strength GWAS findings from 454,473 individuals, and applying Mendelian randomization and Bayesian colocalization analyses, we pinpointed 14 genes that were both dysregulated by ATZ and causally linked to muscular strength. Further interrogation of single-cell/nucleus RNA-sequencing data revealed cell type-specific patterns of 10 reasonable causal genes ( Jund , Limd2 , Ppm1j , Procr , Cdo1 , Irs1 , Kif1b , Nav1 , Nexn , Peak1 ), highlighting the multifaceted cellular processes underlying ATZ-inflicted muscle damage. Notably, Morroniside, with anti-inflammatory and antioxidant properties, rescued several potential therapeutic targets ( Limd2 , Jund , Irs1, Kif1b, Peak1, Nav1 ) and C2C12 myotubes from ATZ-induced atrophy. Collectively, our study sheds light on the effects and molecular underpinnings of ATZ-mediated skeletal muscle toxicity and brings forward viable therapeutic targets and strategy. The multi-omics approach offers a robust framework for translating findings from cell/animal models to human relevance in toxicological research. • Atrazine exposure induces skeletal muscle atrophy in vitro and in vivo. • Atrazine alters fiber composition, reduces stem cells, and causes lipid deposition. • Atrazine induces ROS, NF-κB, protein homeostasis unbalance, and adipogenesis. • Multi-omics identifies 10 causal effect targets and cell type-specific expressions. • Morroniside rescues several targets and counteracts Atrazine toxicity.
Institutions: Westlake University, Soochow University, Second Affiliated Hospital of Soochow University, Zhejiang University, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Zhejiang Chinese Medical University, Zhejiang Shuren University, Second Affiliated Hospital of Zhejiang University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,650
Funders: Westlake University, National Natural Science Foundation of China, China Postdoctoral Science Foundation, Zhejiang Chinese Medical University, Zhejiang Shuren University, National Key Research and Development Program of China, National Key Research and Development Program of China Stem Cell and Translational Research, Natural Science Foundation of Zhejiang Province, Key Research and Development Program of Zhejiang Province
OpenAlex ID: W4414164040