Bmi-1 Overexpression Improves Sarcopenia Induced by 1,25(OH) 2 D 3 Deficiency and Downregulates GATA4-Dependent Rela Transcription.

Sarcopenia increases with age, and an underlying mechanism needs to be determined to help with designing more effective treatments. This study aimed to determine whether 1,25(OH) ₂ D ₃ deficiency could cause cellular senescence and a senescence-associated secretory phenotype (SASP) in skeletal muscle cells to induce sarcopenia, whether GATA4 could be upregulated by 1,25(OH) ₂ D ₃ deficiency to promote SASP, and whether Bmi-1 reduces the expression of GATA4 and GATA4-dependent SASP induced by 1,25(OH) ₂ D ₃ deficiency in skeletal muscle cells. Bioinformatics analyses with RNA sequencing data in skeletal muscle from physiologically aged and young mice were conducted. Skeletal muscles from 2-month-old young and 2-year-old physiologically aged wild-type (WT) mice and 8-week-old WT, Bmi-1 mesenchymal transgene (Bmi-1 ^Tg ), Cyp27b1 homozygous (Cyp27b1 ^-/- ), and Bmi-1 ^Tg Cyp27b1 ^-/- mice were observed for grip strength, cell senescence, DNA damage, and NF-κB-mediated SASP signaling of skeletal muscle. We found that muscle-derived Bmi-1 and vitamin D receptor (VDR) decreased with physiological aging, and DNA damage and GATA4-dependent SASP activation led to sarcopenia. Furthermore, 1,25(OH) ₂ D ₃ deficiency promoted DNA damage-induced GATA4 accumulation in muscles. GATA4 upregulated Rela at the region from -1448 to -1412 bp at the transcriptional level to cause NF-κB-dependent SASP for aggravating cell senescence and muscular dysfunction and sarcopenia. Bmi-1 overexpression promoted the ubiquitination and degradation of GATA4 by binding RING1B, which prevented cell senescence, SASP, and dysfunctional muscle, and improved sarcopenia induced by 1,25(OH) ₂ D ₃ deficiency. Thus, Bmi-1 overexpression improves sarcopenia induced by 1,25(OH) ₂ D ₃ deficiency, downregulates GATA4-dependent Rela transcription, and sequentially inhibits GATA4-dependent SASP in muscle cells. Therefore, Bmi-1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and prevention of sarcopenia. © 2023 American Society for Bone and Mineral Research (ASBMR).
(© 2023 American Society for Bone and Mineral Research (ASBMR).)