Regan, Jenna N.Mikesell, CarterReiken, StevenXu, HaifangMarks, Andrew R.Mohammad, Khalid S.Guise, Theresa A.Waning, David L.2018-06-072018-06-072017-12-19Regan, J. N., Mikesell, C., Reiken, S., Xu, H., Marks, A. R., Mohammad, K. S., … Waning, D. L. (2017). Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model. Frontiers in Endocrinology, 8, 358. http://doi.org/10.3389/fendo.2017.00358https://hdl.handle.net/1805/16387Muscle weakness and cachexia are significant paraneoplastic syndromes of many advanced cancers. Osteolytic bone metastases are common in advanced breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients. Pathologic fracture caused by osteolytic cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture. Since muscle weakness is linked to risk of falls which are a major cause of fracture, we have investigated skeletal muscle response to OCIB. Here, we show that a syngeneic mouse model of OCIB (4T1 mammary tumor cells) leads to cachexia and skeletal muscle weakness associated with oxidation of the ryanodine receptor and calcium (Ca2+) release channel (RyR1). Muscle atrophy follows known pathways via both myostatin signaling and expression of muscle-specific ubiquitin ligases, atrogin-1 and MuRF1. We have identified a mechanism for skeletal muscle weakness due to increased oxidative stress on RyR1 via NAPDH oxidases [NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4)]. In addition, SMAD3 phosphorylation is higher in muscle from tumor-bearing mice, a critical step in the intracellular signaling pathway that transmits TGFβ signaling to the nucleus. This is the first time that skeletal muscle weakness has been described in a syngeneic model of OCIB and represents a unique model system in which to study cachexia and changes in skeletal muscle.en-USAttribution 3.0 United StatesBreast -- CancerImmune competentMuscle weaknessOsteolytic diseaseSyngeneic tumor modelArticle