ArticleThe FEBS journal2025
Hypoxia-induced increase in sphingomyelin synthase 2 aggravates ischemic skeletal muscle inflammation.
Article in The FEBS journal, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Role of Hypoxia-Inducible Factor-1α in Regulating Muscle Degeneration After Rotator Cuff Tears.The American journal of sports medicine · 2026Article
- Identification of a novel metabolic and lipidomic signature for 90-day functional outcome after ischemic stroke: an exploratory proof-of-concept study.Frontiers in neurology · 2026Article
- Sphingomyelin Synthase 2 Deletion Mitigates Oxidative Stress-Induced NF-κB Activation via Lipid Metabolic Reprogramming in Dry Eye Disease.Investigative ophthalmology & visual science · 2025Article
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15 authors.
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Abstract
Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease, posing a high risk of mortality. 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-induced 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 κBα (IκBα), and reduced the nuclear translocation of nuclear factor κB (NFκB) p65. Meanwhile, the administration of sphingomyelin hampered skeletal muscle inflammation by inhibiting IκBα phosphorylation and NFκB p65 nuclear translocation and extending inflammation post-CLI. Our results suggest that hypoxia-induced enhancement in SMS2 levels and the consequent increase in sphingomyelin expression levels promote inflammation in ischemic muscle tissues via the NFκB pathway and propose sphingomyelin as a potential therapeutic target in patients with CLI and other hypoxia-related inflammatory diseases.
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