慢性接触环境砷是影响全球数亿人的公共卫生危机。尽管已知砷对许多疾病和病理产生贡献，包括癌症、心血管和肺部疾病以及神经功能受损，但砷促进疾病的机制仍然未解。而对于砷对骨骼肌功能和代谢的影响尤其如此，尽管骨骼肌健康在维持心血管健康、系统稳态和认知功能方面扮演着关键角色。研究这一领域的障碍是在具有生物学相关性的模型中调查肌细胞特异性效应的挑战。对肌肉特异性反应机制进行的离体研究主要利用传统的二维培养模型，无法阐明对肌肉生理或功能的影响。因此，我们开发了一种收缩性三维肌肉构建模型，由在水凝胶基质中分化的小鼠肌肉前体细胞组成，以研究砷暴露对骨骼肌再生的影响。暴露于低剂量（50 nM）砷的肌肉构建物在肌肉损伤恢复后表现出力量和肌纤维直径降低的效果。这些效应可归因于由肌细胞释放的细胞外囊泡（EVs）介导的细胞间相互作用的失调寄生信号传导。具体而言，我们发现，从砷暴露的肌肉构建物中收集到的EVs再现了直接砷暴露对肌纤维再生的抑制效果。此外，用来自砷暴露小鼠肌肉的EVs处理的肌肉构建物显示出显著降低的力量。我们的研究结果突显了一种用于肌毒性研究的新型模型，并揭示了砷诱导的肌肉功能障碍的机制，即通过破坏EV介导的细胞间通讯。© 作者（们） 2023。由牛津大学出版社代表毒理学会出版。保留所有权利。请发送电子邮件至：journals.permissions@oup.com以获得权限。

Chronic exposure to environmental arsenic is a public health crisis affecting hundreds of millions of individuals worldwide. Though arsenic is known to contribute to many pathologies and diseases, including cancers, cardiovascular and pulmonary diseases, and neurological impairment, the mechanisms for arsenic-promoted disease remain unresolved. This is especially true for arsenic impacts on skeletal muscle function and metabolism, despite the crucial role that skeletal muscle health plays in maintaining cardiovascular health, systemic homeostasis, and cognition. A barrier to researching this area is the challenge of interrogating muscle cell-specific effects in biologically relevant models. Ex vivo studies investigating mechanisms for muscle-specific responses to arsenic or other environmental contaminants primarily utilize traditional two-dimensional culture models that cannot elucidate effects on muscle physiology or function. Therefore, we developed a contractile three-dimensional muscle construct model-composed of primary mouse muscle progenitor cells differentiated in a hydrogel matrix-to study arsenic exposure impacts on skeletal muscle regeneration. Muscle constructs exposed to low-dose (50 nM) arsenic exhibited reduced strength and myofiber diameter following recovery from muscle injury. These effects were attributable to dysfunctional paracrine signaling mediated by extracellular vesicles (EVs) released from muscle cells. Specifically, we found that EVs collected from arsenic-exposed muscle constructs recapitulated the inhibitory effects of direct arsenic exposure on myofiber regeneration. In addition, muscle constructs treated with EVs isolated from muscles of arsenic-exposed mice displayed significantly decreased strength. Our findings highlight a novel model for muscle toxicity research and uncover a mechanism of arsenic-induced muscle dysfunction by the disruption of EV-mediated intercellular communication.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.