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  • br Materials and methods br Results and discussion br


    Materials and methods
    Results and discussion
    Conclusions In the present study, we have shown the important role of miR-204-5p in C2C12 myoblast differentiation. Overexpression of miR-204-5p inhibited myogenic differentiation and decreased the formation of slow-twitch myofibers, whereas miR-204-5p inhibitors had the opposite effect. Our results confirmed that miR-204-5p directly targets the 3′UTR of MEF2C and ERRγ. We found that interference with either MEF2C or ERRγ reduces myoblast differentiation and causes a reduction in slow-twitch myofibers. Meanwhile, either si-MEF2C or si-ERRγ co-transfected with miR-204-5p mimics caused a greater degree of attenuation of myoblast 2-Amino-ATP clinical differentiation. Therefore, we have presented evidence that miR-204-5p regulates myoblast differentiation and muscle fiber types by targeting MEF2C and ERRγ. Our findings suggest that miR-204-5p might serve as a potential regulatory factor that influences myogenesis.
    Declare of conflict interest
    Conflict of interest
    ERR Subfamily Nuclear receptors (NRs) are members of a large family of transcription factors that coordinate and regulate gene 2-Amino-ATP clinical during various cellular processes. Most NRs are ligand dependent. However, there are a few NRs for which appropriate endogenous ligands have not yet been identified; thus, they are defined as orphan NRs. ERRs are orphan receptors consisting of three members, namely, ERRα (NR3B1), ERRβ (NR3B2), and ERRγ (NR3B3) [1]. ERRα and β, which were identified before ERRγ, have been extensively studied 1, 2, 3. ERRγ was first identified through its connection with a critical region of Usher syndrome type IIa [4], and later characterized as a protein interacting with the nuclear receptor coactivator glucocorticoid receptor-interacting protein (GRIP)-1 [5]. It is highly expressed in different fetal and adult human tissues, including the placenta, brain, skeletal muscle, heart, and liver [1]. ERRγ shares the structural features found in other members of the NR superfamily (Figure 1). It contains a N-terminal activation function (AF)-1 domain that is involved in the transcriptional regulation of the receptor and a central zinc finger DNA-binding domain (DBD) that is highly conserved among the three members. Similar to ERRα and β, the DBD of ERRγ binds to the same DNA element, TCAAGGTCA, which is defined as the ERR response element (ERRE). ERRγ also contains a ligand-binding domain (LBD), as well as a C-terminal AF-2 domain that interacts with coactivators and co-repressors [3]. As ERRγ shares nearly identical DBDs with ERRα and β, its transcriptional regulatory functions are likely similar to and overlap with those of ERRα and β in cells where they are coexpressed. For example, both ERRα and ERRγ promote oxidative capacity in skeletal and cardiac muscles 6, 7, 8. The functions of ERRβ and ERRγ are also overlapping; both NRs regulate genes important for ion homeostasis in the heart, kidney, stomach, skeletal muscle, and trophoblasts 9, 10, 11. However, ERRγ also controls metabolic processes, which do not involve ERRα and β 12, 13, 14, 15. Due to the lack of information on the endogenous ligands of ERRγ, synthetic ligands have been developed, such as diethylstilbestrol (DES) and 4-hydroxytamoxifen (4-OHT) that inhibit its activity [16]. Although DES and 4-OHT function as inverse agonists of ERRγ, they are not highly selective, leading to the synthesis of the higher affinity 4-OHT analog, GSK5182, with an IC50 of 79 nM for ERRγ [17]. Additionally, GSK4716, a phenolic acyl hydrazine has been reported as the first ERRβ/γ agonist to activate ERRγ to the same degree as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) [18]. Bisphenol A, a ubiquitous environmental endocrine disruptor also binds to ERRγ with high affinity and can positively regulate the transcriptional activity of human isoform [19]. As these synthetic ligands can affect ERRγ activity in vitro and in vivo, their effects on various pathological conditions are of immense interest.