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Bone Abstracts (2016) 5 CABSOC4.1 | DOI: 10.1530/boneabs.5.CABS.OC4.1

ECTS2016 Cancer and Bone Oral Communications Oral Communications (18 abstracts)

Muscle dysfunction in immune competent mice with osteolytic breast cancer in bone is associated with skeletal muscle oxidation of RyR1

Jenna Regan 1 , David Waning 1 , Khalid Mohammad 1 , Carter Mikesell 1 , Steven Reiken 2 , Andrew Marks 2 & Theresa Guise 1


1Indiana University School of Medicine, Indianapolis, Indiana, USA; 2College of Physicians and Surgeons of Columbia University, New York, New York, USA.


Cancer-associated muscle weakness is an important paraneoplastic syndrome for which there is currently no treatment. Human breast cancer bone metastases (MDA-MB-231 cells in immune deficient mice) induce extensive bone destruction, leading to the release of TGF-β from the bone matrix. We have previously shown that bone-derived TGF-β is responsible for muscle weakness in this model. Mechanistically, TGF-β signaling increases the expression of NADPH oxidase 4 (Nox4), which oxidizes the skeletal muscle ryanodine receptor/calcium release channel (RyR1) leading to sarcoplasmic reticulum (SR) calcium leak. To determine if similar bone-muscle interactions occur with tumor-induced bone destruction in immune competent mice, we injected mouse breast cancer cells (4T1; 100,000 cells) into the tibia of Balb/C mice. The mice rapidly developed osteolytic tumors, weakness and cachexia. Fat and lean content (assessed by DXA) both decreased in mice with 4T1 osteolytic lesions. All ex vivo muscle measurements and molecular analyses were performed on muscle from the limb contralateral to the tumor. Muscle weights (P<0.0001) and fiber cross-sectional area (P=0.005) were lower in mice with osteolytic lesions, an effect potentially driven by the increased expression of the atrophy-associated E3 ubiquitin ligases MuRF1 (P=0.004) and atrogin-1 (P=0.004). Ex vivo contractility of the extensor digitorum longus (EDL) muscle showed a significant reduction (P<0.0001) in specific force in tumor bearing mice compared to controls. Skeletal muscle from tumor bearing mice had higher levels of SMAD3 phosphorylation and Nox4 expression, consistent with increased TGF-β signaling. Finally, the calcium release channel RyR1 was oxidized and depleted of the stabilizing subunit calstabin1. These results echo the biochemical signature we have reported in immune deficient mouse models. Therefore, these data indicate that the phenotype and underlying mechanisms of skeletal muscle weakness in mice with osteolytic breast cancer in the bone are not altered by the immune status of the mice.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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