Polystyrene microplastics induce skeletal muscle atrophy through disruption of anabolic signaling and mitochondrial function

Polystyrene microplastics (PS-MPs) have emerged as pervasive environmental contaminants with growing concerns regarding their potential adverse effects on human health; however, their impact on skeletal muscle homeostasis remains poorly understood. In this study, we investigated the effects of PS-MPs on muscle atrophy and the underlying molecular mechanism using differentiated C2C12 myotubes. Cells were exposed to 1 μm PS-MPs for 24 h, which resulted in a dose-dependent increase in intracellular Reactive Oxygen Species levels at concentrations of 100-500 μg/mL. PS-MPs significantly upregulated the gene and protein expression of muscle atrophy-related markers, including myostatin, atrogin-1, and MuRF1, and increased polyubiquitinated proteins, while markedly suppressed muscle protein synthesis-related markers such as MyoD1, MyoG, and MHC, as well as overall protein synthesis, as determined by puromycin labeling. Mechanistically, PS-MPs remarkably downregulated IGF-1-PI3K-Akt-mTOR signaling pathway, while concomitantly activating AMPK and FoxO3α signaling. Intracellular accumulation of PS-MPs was accompanied by mitochondrial swelling and cristae disruption. Consistently, PS-MPs induced mitochondrial dysfunction, as evidenced by mitochondrial depolarization, decreased ATP production, and reduced expression of PGC-1α, NRF1, TFAM, and OXPHOS proteins. Oxidative stress responses were further characterized by the upregulation of Keap1 and the suppression of NRF2 and HO-1 expression. PS-MPs alone elicited a muscle atrophy phenotype comparable to that caused by dexamethasone, and co-exposure synergistically enhanced the expression of atrogin-1, MuRF1, and myostatin genes. In conclusion, these findings demonstrate that PS-MPs disrupt muscle homeostasis by inhibiting IGF-1-PI3K-Akt signaling, promoting oxidative stress, and impairing mitochondrial integrity, confirming PS-MPs as a previously unrecognized environmental hazard that may contribute to muscle atrophy.