title: Excess TGF-β mediates muscle weakness associated with bone metastases in mice.
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.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Waning
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Sutha
authors.initials: S
authors.lastname: John
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Chiechi
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wright
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Alisa
authors.initials: A
authors.lastname: Umanskaya
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Niewolna
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Trupti
authors.initials: T
authors.lastname: Trivedi
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Sahba
authors.initials: S
authors.lastname: Charkhzarrin
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Khatiwada
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Anetta
authors.initials: A
authors.lastname: Wronska
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Haynes
authors.affiliation: Laboratory of Experimental Oncology, Instituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Benassi
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Witzmann
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gehua
authors.initials: G
authors.lastname: Zhen
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA.
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.affiliation: Department of Physiology and Cellular Biophysics, Helen and Clyde Wu Center for Molecular Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D003966:Camurati-Engelmann Syndrome / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength; D018908:Muscle Weakness / Q000209:etiology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism*; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D055114:X-Ray Microtomography
chemical_list: D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D016212:Transforming Growth Factor beta; C000592747:ryanodine receptor 1, mouse; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse; D002118:Calcium