Perfluorooctanoic acid impairs myogenic differentiation and muscle function via activation of the hippo-YAP pathway in mice and C2C12 myoblasts

• PFOA exposure induces muscle dysfunction in juvenile mice, significantly reducing grip strength and impairing motor coordination. • Long-term PFOA treatment inhibits myogenic differentiation in C2C12 myoblasts, impairing mature myotube formation without affecting cell proliferation. • Transcriptome analysis identifies suppression of key myogenic regulators via Hippo pathway activation, characterized by increased YAP phosphorylation. • Hippo pathway inhibition with taurine rescues myogenic gene expression and restores myotube formation. Perfluorooctanoic acid (PFOA), a widely distributed environmental pollutant, exerts toxic effects on multiple human organs and tissues. However, its impact on skeletal muscle function and the underlying molecular mechanisms remain poorly understood. In this study, we first observed that PFOA exposure caused muscle dysfunction in juvenile mice, characterized by reduced grip strength and impaired motor coordination; to explore the underlying mechanism, we further conducted in vitro experiments using C2C12 myoblasts. Long-term treatment with 100 μM PFOA did not affect C2C12 cell proliferation but significantly inhibited myogenic differentiation, leading to impaired formation of mature myotubes. Transcriptome sequencing revealed a significant decrease in the expression of key myogenic regulatory factors (e.g., myosin heavy chain MYHC and myogenin) in PFOA-treated cells, findings that were confirmed by RT-qPCR and Western blot analyses. Mechanistically, PFOA treatment activated the Hippo signaling pathway, as evidenced by increased phosphorylation of the YAP protein. Treatment with taurine, an indirect activator of YAP, significantly restored the expression of myogenic genes and effectively promoted myotube formation. In summary, this study demonstrates that PFOA impairs muscle function by activating the Hippo signaling pathway and suppressing the transcription of key myogenic factors, providing new insights into PFOA-induced myotoxicity.