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Several molecular defects in skeletal muscle including reduced myoblast determination protein 1 (MyoD) levels and increased protein turn over due to enhanced proteosomal activity have been suggested as causes of skeletal muscle loss in cancer patients. However, it is unknown whether molecular defects in skeletal muscle are dependent on tumour aetiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized functional and molecular defects of skeletal muscle in mouse mammary tumour virus (MMTV)\u2010Neu (Neu+) mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a06\u201312), an animal model that represents HER2\u00a0+\u00a0human breast cancer, and compared the results with well\u2010characterized luminal B breast cancer model MMTV\u2010PyMT (PyMT+). Functional studies such as grip strength, rotarod performance, and <jats:italic>ex vivo<\/jats:italic> muscle contraction were performed to measure the effects of cancer on skeletal muscle. Expression of muscle\u2010enriched genes and microRNAs as well as circulating cytokines\/chemokines were measured. Because nuclear factor\u2010kappaB (NF\u2010\u03baB) pathway plays a significant role in skeletal muscle defects, the ability of NF\u2010\u03baB inhibitor dimethylaminoparthenolide (DMAPT) to reverse skeletal muscle defects was examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Neu+ mice showed skeletal muscle defects similar to accelerated aging. Compared with age and sex\u2010matched wild type mice, Neu+ tumour\u2010bearing mice had lower grip strength (202\u00a0\u00b1\u00a06.9 vs. 179\u00a0\u00b1\u00a06.8\u00a0g grip force, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0069) and impaired rotarod performance (108\u00a0\u00b1\u00a012.1 vs. 30\u00a0\u00b1\u00a03.9\u00a0s, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), which was consistent with reduced muscle contractibility (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001). Skeletal muscle of Neu+ mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a06) contained lower levels of CD82\u00a0+\u00a0(16.2\u00a0\u00b1\u00a02.9 vs. 9.0\u00a0\u00b1\u00a01.6) and CD54\u00a0+\u00a0(3.8\u00a0\u00b1\u00a00.5 vs. 2.4\u00a0\u00b1\u00a00.4) muscle stem and progenitor cells (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), suggesting impaired capacity of muscle regeneration, which was accompanied by decreased MyoD, p53, and miR\u2010486 expression in muscles (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Unlike PyMT+ mice, which showed skeletal muscle mitochondrial defects including reduced mitochondria levels and peroxisome proliferator\u2010activated receptor gamma co\u2010activator 1 (beta), Neu\u00a0+\u00a0mice displayed accelerated aging\u2010associated changes including muscle fibre shrinkage and increased extracellular matrix deposition. Circulating \u2018aging factor\u2019 and cachexia and fibromyalgia\u2010associated chemokine C\u2010C motif chemokine ligand 11 (Ccl11) was elevated in Neu+ mice (1439.56\u00a0\u00b1\u00a0514 vs. 1950\u00a0\u00b1\u00a0345\u00a0pg\/mL, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Treatment of Neu+ mice with DMAPT significantly restored grip strength (205\u00a0\u00b1\u00a06\u00a0g force), rotarod performance (74\u00a0\u00b1\u00a08.5\u00a0s), reversed molecular alterations associated with skeletal muscle aging, reduced circulating Ccl11 (1083.26\u00a0\u00b1\u00a0478\u00a0pg\/mL), and improved animal survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that breast cancer subtype has a specific impact on the type of molecular and structural changes in skeletal muscle, which needs to be taken into consideration while designing therapies to reduce breast cancer\u2010induced skeletal muscle loss and functional limitations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/rco2.23","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T13:59:23Z","timestamp":1594821563000},"page":"24-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Aging\u2010associated skeletal muscle defects in HER2\/Neu transgenic mammary tumour model"],"prefix":"10.1002","volume":"4","author":[{"given":"Ruizhong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Surgery Indiana University School of Medicine  Indianapolis IN 46202 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brijesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Surgery Indiana University School of Medicine  Indianapolis IN 46202 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