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FTO-mediated demethylation of GADD45B promotes myogenesis through the activation of p38 MAPK pathway.

ABSTRACT: N6-methyladenosine (m⁶A) modification plays a critical role in mammalian development. However, the role of m⁶A in the skeletal muscle development remains largely unknown. Here, we report a global m⁶A modification pattern of goat skeletal muscle at two key development stages and identified that the m⁶A modification regulated the expression of the growth arrest and DNA damage-inducible 45B (GADD45B) gene, which is involved in myogenic differentiation. We showed that GADD45B expression increased during myoblast differentiation, whereas the downregulation of GADD45B inhibits myogenic differentiation and mitochondrial biogenesis. Moreover, the expression of GADD45B regulates the expression of myogenic regulatory factors and peroxisome proliferator-activated receptor gamma coactivator 1 alpha by activating the p38 mitogen-activated protein kinase (MAPK) pathway. Conversely, the inactivation of p38 MAPK abolished the GADD45B-mediated myogenic differentiation. Furthermore, we found that the knockdown of fat mass and obesity-associated protein (FTO) increases GADD45B m⁶A modification and decreases the stability of GADD45B mRNA, which impairs myogenic differentiation. Our results indicate that the FTO-mediated m⁶A modification in GADD45B mRNA drives skeletal muscle differentiation by activating the p38 MAPK pathway, which provides a molecular mechanism for the regulation of myogenesis via RNA methylation.

SUBMITTER: Deng K

PROVIDER: S-EPMC8408560 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ubiquitin D (UBD), a member of the ubiquitin‑like modifier family, has been reported to be highly expressed in various types of cancer and its overexpression is positively associated with tumor progression. However, the role and mechanism of UBD in rheumatoid arthritis (RA) remain elusive. In the present study, the gene expression profiles of GSE55457 were downloaded from the Gene Expression Omnibus database to assess differentially expressed genes and perform functional enrichment analyses. UBD was overexpressed by lentivirus transfection. The protein level of UBD, p‑p38 and p38 in RA‑fibroblast‑like synoviocytes (FLSs) were examined by western blotting. Cell Counting Kit‑8 and flow cytometry assays were used to detect the functional changes of RA‑FLSs transfected with UBD and MAPK inhibitor SB202190. The concentrations of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α) were evaluated using ELISA kits. The results revealed that UBD was overexpressed in RA tissues compared with in the healthy control tissues. Functionally, UBD significantly accelerated the viability and proliferation of RA‑FLSs, whereas it inhibited their apoptosis. Furthermore, UBD significantly promoted the secretion of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α). Mechanistically, elevated UBD activated phospohorylated‑p38 in RA‑FLSs. By contrast, UBD overexpression and treatment with the p38 MAPK inhibitor SB202190 not only partially relieved the UBD‑dependent effects on cell viability and proliferation, but also reversed its inhibitory effects on cell apoptosis. Furthermore, SB202190 partially inhibited the effects of UBD overexpression on the enhanced secretion of inflammatory factors. The present study indicated that UBD may mediate the activation of p38 MAPK, thereby facilitating the proliferation of RA‑FLSs and ultimately promoting the progression of RA. Therefore, UBD may be considered a potential therapeutic target and a promising prognostic biomarker for RA.

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FTO-mediated demethylation of GADD45B promotes myogenesis through the activation of p38 MAPK pathway.

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