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Among many cellular and metabolic alterations caused by HHcy, oxidative and endoplasmic reticulum (ER) stress are considered the major ones; however, the precise molecular mechanism(s) in this process is unclear. Nevertheless, there is no treatment option available to treat HHcy-mediated muscle injury. Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) is increasingly recognized as a potent anti-oxidant, anti-apoptotic\/necrotic\/pyroptotic, and anti-inflammatory compound and also has been shown to improve angiogenesis during ischemic injury. Patients with CBS mutation produce less H<jats:sub>2<\/jats:sub>S, making them vulnerable to Hcy-mediated cellular damage. Many studies have reported bidirectional regulation of ER stress in apoptosis through JNK activation and concomitant attenuation of cell proliferation and protein synthesis via PI3K\/AKT axis. Whether H<jats:sub>2<\/jats:sub>S mitigates these detrimental effects of HHcy on muscle remains unexplored. In this review, we discuss molecular mechanisms of HHcy-mediated oxidative\/ER stress responses, apoptosis, angiogenesis, and atrophic changes in skeletal muscle and how H<jats:sub>2<\/jats:sub>S can restore skeletal muscle homeostasis during HHcy condition. This review also highlights the molecular mechanisms on how H<jats:sub>2<\/jats:sub>S could be developed as a clinically relevant therapeutic option for chronic conditions that are aggravated by HHcy. <\/jats:p>","DOI":"10.1139\/cjpp-2018-0501","type":"journal-article","created":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T21:39:23Z","timestamp":1542145163000},"page":"441-456","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative\/ER stress condition"],"prefix":"10.1139","volume":"97","author":[{"given":"Avisek","family":"Majumder","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA."},{"name":"Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40202, 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