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 the following: 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, and to determine whether GATA4 could be upregulated by 1,25(OH) 2 D 3 deficiency to promote SASP. Also, 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 two-month-old young and two-year-old physiologically aged wild-type mice, and eight-week-old wildtype, Bmi-1 mesenchymal transgene (Bmi-1 Tg ), Cyp27b1 homozygous (Cyp27b1 -/- ), and Bmi-1 Tg Cyp27b1 -/- mice were observed the grip strength, cell senescence, DNA damage and NF-κB-mediated SASP signaling of skeletal muscle. We found that muscle-derived Bmi-1 and 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 rescued cell senescence, SASP and dysfunctional muscle, also 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 and downregulates GATA4-dependent Rela transcription, and sequentially inhibiting GATA4-dependent SASP in muscle cells. Therefore, Bmi-1 overexpression could be used for translational gene therapy for the ubiquitination of GATA4 and preventing sarcopenia. This article is protected by copyright. All rights reserved.