Polystyrene nanoplastics promote muscle cell senescence through microtubule hyper-stabilization-mediated mitophagy dysfunction and cGAS-Sting activation

The detrimental effects of polystyrene nanoplastics (NPs) on human skeletal muscle cells and underlying mechanisms remain largely unclear. Here we exposed mice to NPs and observed significant NP uptake and damages in muscles. RNA sequencing result revealed that many cytoskeleton-related factors were markedly altered by NPs. With cultured human muscle cells, we demonstrate that internalized NPs profoundly changed the microtubule network by causing increased tubulin acetylation, enhanced stabilization, and reduced dynamics. These microtubule changes were accompanied by impaired microtubule-organizing center (MTOC) functionality, defective mechanotransduction capacity linked to YAP deactivation, and critically, compromised function as trafficking tracks for intracellular organelles like mitochondria and lysosomes, leading to accumulation of damaged mitochondria and dysfunctional mitophagy at MTOC location. mtDNA leakage from damaged mitochondria then led to cGAS-Sting activation and accelerated cellular senescence. Mechanistically, NP-induced microtubule hyper-stabilization was driven by deactivation of tubulin deacetylases Sirt2 and HDAC6, leading to α-tubulin hyperacetylation. Further, Sirt2 reactivation/overexpression in muscle cells effectively reduced NP-induced α-tubulin acetylation, mitochondrial damage, cGAS-Sting activation and cellular senescence, as well as the level of cytoplasmic NPs. Our findings unveil a novel mechanism by which NPs promote cellular senescence, highlighting microtubule dynamics as a key mediator of NP-induced damage and a promising therapeutic target.