Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

中文翻译：

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转移性癌症通过骨骼肌中 Z​​IP14 上调促进恶病质。


患有转移性癌症的患者会经历骨骼肌质量和功能的严重丧失，称为恶病质。恶病质与癌症患者的不良预后和加速死亡有关，但其潜在机制仍知之甚少。在这里，我们确定金属离子转运蛋白 ZRT 和 IRT 样蛋白 14 (ZIP14) 是癌症引起的恶病质的关键介质。 ZIP14 在小鼠恶病质肌肉和转移性癌症患者中表达上调，并且可由 TNF-α 和 TGF-β 细胞因子诱导。引人注目的是，生殖系消融或 Zip14 的肌肉特异性耗竭可显着减少转移性癌症模型中的肌肉萎缩。我们发现肌肉祖细胞中 ZIP14 介导的锌摄取抑制 MyoD 和 Mef2c 的表达并阻止肌肉细胞分化。重要的是，ZIP14 介导的分化肌肉细胞中的锌积累会诱导肌球蛋白重链丢失。这些结果强调了锌稳态改变在转移性癌症引起的肌肉萎缩中的先前未被认识的作用，并暗示 ZIP14 作为其治疗的治疗靶点。