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Sphingomyelin, a sphingolipid synthesized by sphingomyelin synthases (SMSs) 1 and 2, plays an essential role in signal transduction as a component of lipid rafts. However, the role of sphingomyelin in the inflammation of ischemic skeletal muscles remains unclear. In this study, we analyzed the roles of sphingomyelin and SMSs in CLI\u2010induced myopathy using a mouse hindlimb ischemia model. We observed that hypoxia after CLI triggered an increase in SMS2 levels, thereby elevating sphingomyelin concentrations in ischemic skeletal muscles. The expression of SMS2 and sphingomyelin was induced by hypoxia in C2C12 myotubes and regulated by the prolyl hydroxylase domain enzyme. Additionally, SMS2 deficiency suppressed skeletal muscle inflammation after CLI, attenuated the phosphorylation of inhibitor of \u03baB\u03b1 (I\u03baB\u03b1), and reduced the nuclear translocation of nuclear factor \u03baB (NF\u03baB) p65. Meanwhile, the administration of sphingomyelin hampered skeletal muscle inflammation by inhibiting I\u03baB\u03b1 phosphorylation and NF\u03baB p65 nuclear translocation and extending inflammation post\u2010CLI. Our results suggest that hypoxia\u2010induced enhancement in SMS2 levels and the consequent increase in sphingomyelin expression levels promote inflammation in ischemic muscle tissues via the NF\u03baB pathway and propose sphingomyelin as a potential therapeutic target in patients with CLI and other hypoxia\u2010related inflammatory diseases.<\/jats:p>","DOI":"10.1111\/febs.17379","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T06:00:02Z","timestamp":1735538402000},"page":"1086-1105","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hypoxia\u2010induced increase in sphingomyelin synthase 2 aggravates ischemic skeletal muscle inflammation"],"prefix":"10.1111","volume":"292","author":[{"given":"Hinano","family":"Mizugaki","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine Azabu University  Sagamihara 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