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However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in na\u00efve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>Min\/+<\/jats:sup>\n                    mouse models of cancer cachexia. Treatment of mice with 4\u2010phenylbutyrate (4\u2010PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC\u2010bearing mice. Blocking the UPR also increased the proportion of fast\u2010type fibers in soleus muscle of both control and LLC\u2010bearing mice. Inhibition of UPR reduced the activity of Akt\/mTOR pathway and increased the expression of the components of the ubiquitin\u2013proteasome system and autophagy in LLC\u2010bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.\u2014Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. FASEB J. 30, 3053\u20133068 (2016).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201600250rr","type":"journal-article","created":{"date-parts":[[2016,5,23]],"date-time":"2016-05-23T00:21:39Z","timestamp":1463962899000},"page":"3053-3068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia"],"prefix":"10.1096","volume":"30","author":[{"given":"Kyle R.","family":"Bohnert","sequence":"first","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann S.","family":"Gallot","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajedah M.","family":"Hindi","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences and Neurobiology University of Louisville School of Medicine  Louisville Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.011"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.05.032"},{"key":"e_1_2_7_5_1","article-title":"Protein breakdown in cancer cachexia. 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