Excess TGF-β mediates muscle weakness associated with bone metastases in mice

David L. Waning, Khalid S. Mohammad, Steven Reiken, Wenjun Xie, Daniel C. Andersson, Sutha John, Antonella Chiechi, Laura E. Wright, Alisa Umanskaya, Maria Niewolna, Trupti Trivedi, Sahba Charkhzarrin, Pooja Khatiwada, Anetta Wronska, Ashley Haynes, Maria Serena Benassi, Frank A. Witzmann, Gehua Zhen, Xiao Wang, Xu CaoG. David Roodman, Andrew R. Marks, Theresa A. Guise

Research output: Contribution to journalArticle

Abstract

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)-β, 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-β signaling, TGF-β 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-β activity. Thus, pathological TGF-β release from bone contributes to muscle weakness by decreasing Ca 2+ -induced muscle force production.

Original languageEnglish
Pages (from-to)1262-1271
Number of pages10
JournalNature Medicine
Volume21
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Waning, D. L., Mohammad, K. S., Reiken, S., Xie, W., Andersson, D. C., John, S., Chiechi, A., Wright, L. E., Umanskaya, A., Niewolna, M., Trivedi, T., Charkhzarrin, S., Khatiwada, P., Wronska, A., Haynes, A., Benassi, M. S., Witzmann, F. A., Zhen, G., Wang, X., ... Guise, T. A. (2015). Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nature Medicine, 21(11), 1262-1271. https://doi.org/10.1038/nm.3961