Arsenic disrupts extracellular vesicle-mediated signaling in regenerating myofibers.
Arsenic disrupts extracellular vesicle-mediated signaling in regenerating myofibers.
复制标题
砷会破坏肌纤维再生过程中细胞外囊泡介导的信号传导。
DOI：
10.1093/toxsci/kfad075
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Barchowsky,Aaron
中科院分区：
文献类型：
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作者：
Clemens,Zachary;Wang,Kai;Ambrosio,Fabrisia;Barchowsky,Aaron
长期暴露于环境中的砷是一个公共卫生危机，影响到全世界数亿人。虽然已知砷会导致许多病理和疾病，包括癌症、心血管和肺部疾病以及神经损伤，但砷促进疾病的机制仍未得到解决。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、全身稳态和认知方面发挥着至关重要的作用。研究这一领域的一个障碍是在生物学相关models.Ex vivostudies调查机制的肌肉特异性反应砷或其他环境污染物的肌肉细胞特异性的质疑的挑战，主要利用传统的二维培养模型，不能阐明对肌肉生理或功能的影响。因此，我们开发了一种可收缩的三维肌肉结构模型-由在水凝胶基质中分化的原代小鼠肌肉祖细胞组成-来研究砷暴露对骨骼肌再生的影响。肌肉结构暴露于低剂量（50纳米）砷表现出减少的强度和肌纤维直径后恢复肌肉损伤。这些效应归因于由肌细胞释放的细胞外囊泡（EV）介导的功能失调的旁分泌信号传导。具体来说，我们发现，从砷暴露的肌肉结构收集的EV概括了直接砷暴露对肌纤维再生的抑制作用。此外，用从砷暴露小鼠肌肉中分离的EV处理的肌肉结构显示出显著降低的强度。我们的研究结果强调了一种新的模型，肌肉毒性研究和揭示砷诱导的肌肉功能障碍的机制，通过破坏EV介导的细胞间通讯。
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 vivostudies investigating mechanisms for muscle-specific responses to arsenic or other environmental contaminants primarily utilize traditional 2-dimensional culture models that cannot elucidate effects on muscle physiology or function. Therefore, we developed a contractile 3-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.