Pauk Martina, Wang Fan, Rummukainen Petri, Ramm H G Mauricio, Taipaleenmäki Hanna, Kiviranta Riku
Institute of Biomedicine, University of Turku, Turku, Finland.
Institute of Musculoskeletal Medicine, LMU University Hospital, LMU Munich, Munich, Germany.
Cell Death Discov. 2025 Jul 1;11(1):298. doi: 10.1038/s41420-025-02568-9.
RCOR proteins belong to a family of highly conserved transcription corepressors (RCOR1, RCOR2 and RCOR3) that regulate the activity of associated histone demethylase 1 (LSD1) and histone deacetylase 1/2 (HDAC 1/2) in chromatin-modifying complexes. Despite the described function of LSD1 in skeletal muscle differentiation and regeneration, the role of RCOR family in myogenesis remains unknown. We found that RCOR1 is highly expressed in proliferating myoblasts and activated satellite cells, but not in mature myofibers during postnatal skeletal muscle growth and regeneration. Silencing of RCOR1 impaired myoblast differentiation and fusion, as evidenced by reduced levels of myogenin and MyHC, key markers of myogenic commitment. Moreover, RCOR1 depletion impaired myoblast proliferation through upregulation of the cell cycle inhibitor P21. Although combined silencing of P21 and RCOR1 rescued the proliferation defect of RCOR1 deficiency alone, it failed to restore differentiation, suggesting that RCOR1 action on myoblast proliferation and differentiation is mediated via independent mechanisms. RCOR1 was found physically associated with LSD1 and myogenic regulatory factor MyoD and contributed to LSD1 stability in myoblasts via ubiquitination. Accordingly, the repressive effect of RCOR1 depletion on myogenic differentiation was rescued by LSD1 overexpression, indicating that RCOR1 exerts its function on myoblast differentiation primarily through LSD1. Consistently, in a mouse model of skeletal muscle injury, depletion of RCOR1, accompanied with reduction of LSD1, supressed satellite cell activation and differentiation which resulted in impaired muscle regeneration. Together, our findings indicate that RCOR1 acts in concert with LSD1 as a novel positive regulator of myogenesis and skeletal muscle regeneration.
RCOR蛋白属于一类高度保守的转录共抑制因子家族（RCOR1、RCOR2和RCOR3），它们在染色质修饰复合物中调节相关组蛋白去甲基化酶1（LSD1）和组蛋白脱乙酰基酶1/2（HDAC 1/2）的活性。尽管已描述了LSD1在骨骼肌分化和再生中的功能，但RCOR家族在肌生成中的作用仍不清楚。我们发现，在出生后骨骼肌生长和再生过程中，RCOR1在增殖的成肌细胞和活化的卫星细胞中高表达，但在成熟肌纤维中不表达。RCOR1的沉默损害了成肌细胞的分化和融合，肌生成关键标志物肌细胞生成素和肌球蛋白重链（MyHC）水平降低证明了这一点。此外，RCOR1的缺失通过上调细胞周期抑制剂P21损害了成肌细胞的增殖。尽管联合沉默P21和RCOR1挽救了单独RCOR1缺失导致的增殖缺陷，但未能恢复分化，这表明RCOR1对成肌细胞增殖和分化的作用是通过独立机制介导的。发现RCOR1与LSD1和肌生成调节因子MyoD在物理上相关，并通过泛素化作用促进成肌细胞中LSD1的稳定性。因此，LSD1的过表达挽救了RCOR1缺失对肌生成分化的抑制作用，表明RCOR1主要通过LSD1对成肌细胞分化发挥作用。同样，在骨骼肌损伤的小鼠模型中，RCOR1的缺失伴随着LSD1的减少，抑制了卫星细胞的激活和分化，导致肌肉再生受损。总之，我们的研究结果表明，RCOR1与LSD1协同作用，作为肌生成和骨骼肌再生的新型正调控因子。
