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Nat Med ; 21(11): 1262-1271, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26457758

RESUMEN

Cancer-associated muscle weakness is a poorly understood phenomenon, and there is no effective treatment. Here we find that seven different mouse models of human osteolytic bone metastases-representing breast, lung and prostate cancers, as well as multiple myeloma-exhibited impaired muscle function, implicating a role for the tumor-bone microenvironment in cancer-associated muscle weakness. We found that transforming growth factor (TGF)-ß, released from the bone surface as a result of metastasis-induced bone destruction, upregulated NADPH oxidase 4 (Nox4), resulting in elevated oxidization of skeletal muscle proteins, including the ryanodine receptor and calcium (Ca(2+)) release channel (RyR1). The oxidized RyR1 channels leaked Ca(2+), resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-ß signaling, TGF-ß release from bone or Nox4 activity improved muscle function in mice with MDA-MB-231 bone metastases. Humans with breast- or lung cancer-associated bone metastases also had oxidized skeletal muscle RyR1 that is not seen in normal muscle. Similarly, skeletal muscle weakness, increased Nox4 binding to RyR1 and oxidation of RyR1 were present in a mouse model of Camurati-Engelmann disease, a nonmalignant metabolic bone disorder associated with increased TGF-ß activity. Thus, pathological TGF-ß release from bone contributes to muscle weakness by decreasing Ca(2+)-induced muscle force production.


Asunto(s)
Neoplasias Óseas/metabolismo , Calcio/metabolismo , Debilidad Muscular/metabolismo , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Osteólisis/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Absorciometría de Fotón , Animales , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Señalización del Calcio , Síndrome de Camurati-Engelmann/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células MCF-7 , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Contracción Muscular , Proteínas Musculares/metabolismo , Fuerza Muscular , Debilidad Muscular/etiología , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Neoplasias/complicaciones , Neoplasias/patología , Osteólisis/diagnóstico por imagen , Osteólisis/etiología , Oxidación-Reducción , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba , Microtomografía por Rayos X
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