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The imbalance of protein synthesis and degradation which jeopardizes immune, hormone regulation, and muscle\u2010motor neuron connection is the main cause of sarcopenia. There is limited knowledge regarding molecular mechanism of sarcopenia. As the endoplasmic reticulum is the control centre of the protein syntheses and degradation, we hypothesized that endoplasmic reticulum stress and unfolded protein response (UPR) play an important in the development of sarcopenia. Understanding the sarcopenia molecular mechanisms may benefit the therapeutic diagnosis and treatment in the future.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mouse myoblast C2C12 cells are exposed to designated time and concentration of indoxyl sulfate (IS), a uremic toxin of chronic kidney disease. The proliferation, differentiation, and the expression of atrogin 1 are examined. The protein and mRNA expression of IS treated\u2010C2C12 cells are inspected to distinguish the role of ER stress and oxidative stress underlying the sarcopenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Indoxyl sulfate inhibits myoblast differentiation. We demonstrate that as the number of multi\u2010nuclei myotube decreased, the differentiation markers including myoD, myoG, and myosin heavy chain are also suppressed. Indoxyl sulfate inhibits myoblast proliferation and induces the myotubular atrophy marker atrogin\u20101 protein expression. Indoxyl sulfate stimulates eIF2\u03b1 phosphorylation and XBP1 mRNA splicing in UPR. Interestingly, the oxidative stress is related to eIF2\u03b1 phosphorylation but not XBP1 mRNA splicing. The eIF2\u03b1 phosphorylation triggered by IS reduces myoD, myoG, and myosin heavy chain protein expression, which represents the anti\u2010myogenic modulation on the early differentiation event. The XBP1 mRNA splicing induced by IS, however, is considered the adaptive response to restore the myogenic differentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our studies indicated that the ER stress and UPR modulation are critical in the chronic kidney disease uremic toxin\u2010accumulated sarcopenia model. We believe that UPR\u2010related signals showed great potential in clinical application.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12288","type":"journal-article","created":{"date-parts":[[2018,1,30]],"date-time":"2018-01-30T03:00:41Z","timestamp":1517281241000},"page":"570-584","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The double\u2010edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation"],"prefix":"10.1002","volume":"9","author":[{"given":"Jia\u2010Rong","family":"Jheng","sequence":"first","affiliation":[{"name":"Graduate Institute of Toxicology, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Department of Internal Medicine, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Siao","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate 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