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

被引：289

作者：

Waning, David L. ^{[1
]}

Mohammad, Khalid S. ^{[1
]}

Reiken, Steven ^{[2
]}

Xie, Wenjun ^{[2
]}

Andersson, Daniel C. ^{[2
]}

John, Sutha ^{[1
]}

Chiechi, Antonella ^{[1
]}

Wright, Laura E. ^{[1
]}

Umanskaya, Alisa ^{[2
]}

Niewolna, Maria ^{[1
]}

Trivedi, Trupti ^{[1
]}

Charkhzarrin, Sahba ^{[1
]}

Khatiwada, Pooja ^{[1
]}

Wronska, Anetta ^{[2
]}

Haynes, Ashley ^{[2
]}

Benassi, Maria Serena ^{[3
]}

Witzmannt, Frank A. ^{[4
]}

Zhen, Gehua ^{[5
]}

Wang, Xiao ^{[5
]}

Cao, Xu ^{[5
]}

Roodman, G. David ^{[6
,7
]}

Marks, Andrew R. ^{[2
]}

Guise, Theresa A. ^{[1
]}

机构：

[1] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA

[2] Columbia Univ Coll Phys & Surg, Dept Physiol & Cellular Biophys, Helen & Clyde Wu Ctr Mol Cardiol, New York, NY 10032 USA

[3] Inst Ortoped Rizzoli, Expt Oncol Lab, Bologna, Italy

[4] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA

[5] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD USA

[6] Indiana Univ Sch Med, Div Hematol & Oncol, Dept Med, Indianapolis, IN 46202 USA

[7] Richard L Roudebush Virginia Med Ctr, Indianapolis, IN USA

来源：

NATURE MEDICINE | 2015年 / 21卷 / 11期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-BETA; CAMURATI-ENGELMANN-DISEASE; HORMONE-RELATED PROTEIN; RYANODINE RECEPTOR; INTRACELLULAR CALCIUM; DYSTROPHIC MUSCLE; CANCER CACHEXIA; IN-VIVO; RELEASE; CELLS;

D O I：

10.1038/nm.3961

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)-beta, 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 (Ca2+) release channel (RyR1). The oxidized RyR1 channels leaked Ca2+, resulting in lower intracellular signaling, which is required for proper muscle contraction. We found that inhibiting RyR1 leakage, TGF-beta signaling, TGF-beta 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-beta activity. Thus, pathological TGF-beta release from bone contributes to muscle weakness by decreasing Ca2+-induced muscle force production.

引用

页码：1262 / 1271

页数：10