Metastatic cancers promote cachexia through altered zinc homeostasis in skeletal muscle

Metastatic cancer patients experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in cancer patients, yet its underlying mechanisms remain poorly understood. Here, we identify the metal transporter ZIP14 as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles from mice and patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, in vivo manipulation of Zip14 expression has profound impact on muscle atrophy in experimental models of metastasis. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of the key myogenic factors 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 muscle during metastatic-cancer-induced cachexia, and implicate ZIP14 as a therapeutic target for its treatment.