The role of retinol saturase enzyme and adenosine A3 receptor in skeletal muscle development and regeneration

dc.contributor.advisorSarang, Zsolt
dc.contributor.authorTarban, Nastaran
dc.contributor.departmentMolekuláris sejt- és immunbiológia doktori iskolahu
dc.contributor.submitterdepÁltalános Orvostudományi Kar
dc.date.accessioned2024-06-28T05:27:52Z
dc.date.available2024-06-28T05:27:52Z
dc.date.created2024
dc.date.defended2024-07-16
dc.description.abstractFollowing skeletal muscle injury, the regeneration begins with local inflammation, which is accompanied by the removal of dead cells. Phagocytosis of dead cells regulates the inflammatory program in macrophages (Mϕ) by promoting the transformation of inflammatory macrophages into “healing” macrophages. The pro-inflammatory cytokines initiate the activation and proliferation of muscle stem cells, called satellite cells, while growth factors, produced by healing macrophages drive myoblast differentiation, fusion, and myotube growth. Therefore, impaired phagocytosis or inflammation can lead to decreased muscle regeneration. The oxidoreductase enzyme retinol saturase (RetSat) is required for proper Mϕ phagocytosis while A3 adenosine receptor (A3R) was shown to modulate inflammatory responses. Therefore, our aim was to investigate the impact of RetSat enzyme and A3R deficiency on skeletal muscle development and regeneration in mice. Tibialis anterior (TA) muscle damage was induced by intramuscular cardiotoxin (CTX) injection. Muscle fiber cross-sectional area (CSA), collagen deposition, and the extent of tissue necrosis were measured to evaluate the regeneration process. Flow cytometric analysis was used to quantify intramuscular leukocyte infiltration and detect SCs. Gene expression was measured in total muscles and muscle-infiltrating CD45+ cells. In vivo muscle force measurements were used to determine the impact of A3R ablation on physical performance. We found that RetSat ablation did not affect the body and TA muscle weights. In addition, the structure and the fiber size of the regenerating muscles ultimately were similar in both strains. In accordance with the previous findings, the in vitro phagocytosis assay showed lower phagocytic capacity of the Mϕs in RetSat−/− mice. Parallel with this, we detected decreased milk fat globule-EGF factor 8 protein (MFG-E8), arginase 1, and neuropeptide Y expression and increased IL1-β and nitric oxide synthase expression in muscle-derived CD45+ in RetSat−/− mice. There was a decreased CD45+ cell infiltration in the regenerating muscles of RetSat−/− mice. However, the size of the necrotic areas in the regenerating TA muscles was similar between the two mouse strains. In line with this, we detected a robust MFG-E8 expression in the regenerating TA muscles of both strains. A3R ablation did not affect body and muscle weights, but a higher percentage of bigger muscle fibers was detected in fast twitch muscles of A3R−/− mice, as well as decreased muscle strength in mice. There was an increased CD45+ cell infiltration in the regenerating muscles of A3R−/− mice and these mice exhibited a more rapid clearance of necrotic tissue and a reduced collagen 1 deposition during TA muscle regeneration. Moreover, we detected a significantly increased myofiber CSA in the regenerating muscles of A3R−/− mice at day 22 post-injury. We have found that in the RetSat−/− mice, there are multiple compensatory mechanisms between the cells that participate in the skeletal muscle regeneration which ultimately results in normal muscle repair in the absence of RetSat enzyme despite the observed decreased Mϕ function. In the case of adenosine A3R, our data support the role of this receptor as a negative regulator of both injury-related regenerative inflammation and muscle fiber growth in the TA muscle. Consequently, the inhibition of A3R may hold therapeutic promise for enhancing skeletal muscle regeneration after injury.
dc.format.extent96
dc.identifier.urihttps://hdl.handle.net/2437/375098
dc.language.isoen
dc.subjectmuscle regeneration
dc.subjectinflammation
dc.subjectmacrophages
dc.subject.disciplineElméleti orvostudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleThe role of retinol saturase enzyme and adenosine A3 receptor in skeletal muscle development and regeneration
dc.title.translatedA retinol szaturáz enzim és az adenozin A3 receptor szerepe a vázizomzat fejlődésében és regenerációjában
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