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Dystrobrevin Alpha Gene Is a Direct Target of the Vitamin D Receptor in Muscle

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Dystrobrevin Alpha Gene Is a Direct Target of the Vitamin D Receptor in Muscle 64 3 Journal of Molecular M K Tsoumpra et al. Upregulation of dystrobrevin by 64:3 195–208 Endocrinology calcitriol RESEARCH Dystrobrevin alpha gene is a direct target of the vitamin D receptor in muscle Maria K Tsoumpra1, Shun Sawatsubashi2, Michihiro Imamura1, Seiji Fukumoto2, Shin’ichi Takeda1, Toshio Matsumoto2 and Yoshitsugu Aoki1 1Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan 2Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan Correspondence should be addressed to S Fukumoto: [email protected] Abstract The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its Key Words tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which f vitamin D functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response f muscle elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle f gene regulation cells occurs concomitantly with transcriptional regulation of key myogenic factors upon f receptor binding VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1–50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in Journal of Molecular treatments aiming to stabilize the DAPC in musculoskeletal diseases. Endocrinology (2020) 64, 195–208 Introduction The biologically active metabolite of vitamin D, genomic sequences called vitamin D response elements 1,25-dihydroxyvitamin D3 (VD3), is a calcium regulating (VDREs) to influence gene transcription (Umesono et al. hormone that exerts its tissue-specific biological actions 1991, Kliewer et al. 1992). through binding to its intracellular vitamin D receptor A link of murine VDR implication in transcriptional (VDR) (Kato 2000). Once VD3 binds to VDR, dimerization downregulation of myogenic factors during skeletal with one of the three retinoid X receptors (RXRα, muscle development has been initially reported by RXRβ, and RXRγ) occurs, and the VDR-RXR dimer can our team (Endo et al. 2003), suggesting that VDR can translocate to the nucleus where it recognizes specific partially mediate the course of myogenic differentiation. https://jme.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/JME-19-0229 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 04:28:31AM via free access -19-0229 Journal of Molecular M K Tsoumpra et al. Upregulation of dystrobrevin by 64:3 196 Endocrinology calcitriol In vitro studies using murine C2C12 muscle cells backed motif interaction (Sadoulet-Puccio et al. 1997), whereas its up the existence of a dose-dependent anti-proliferative N-terminal domain directly interacts with sarcoglycan and effect of VD3 that increased myotube size, which was sarcospan subcomplex (Yoshida et al. 2000). Absence of C accompanied by downregulation of myostatin, a negative terminal dystrophin binding motif does not prevent DTNA regulator of muscle mass (Garcia et al. 2011, Girgis et al. binding to the DAPC, indicating that an unidentified 2014a). The same group demonstrated the presence of an anchoring site is present in the N-terminal region of Dtna autoregulatory vitamin D-endocrine system in skeletal (Crawford et al. 2000). In addition, DTNA colocalizes at muscle (Girgis et al. 2014a), although the VDR muscle- the sarcolemma with dysbindin (Benson et al. 2001), at the specific expression was reported to be much lower than neuromuscular junction with syncoilin (Newey et al. 2001), that measured in other specific tissues such as intestine and binds desmuslin (Mizuno et al. 2001) and syntrophins (Bouillon et al. 2014). VDR expression was found elevated (Ahn et al. 1996). in tibialis anterior muscle obtained from mice treated daily The murine Dtna gene is located on chromosome 18 with VD3 via i.m. injection on days 4–7 post-mechanical consists of 24 coding exons and is subjected to extensive injury, which suggests the presence of local synthesis and alternative splicing that produces tissue-specific isoforms regulation of VD3 metabolism during muscle regeneration (Blake et al. 1996, Ambrose et al. 1997). Overall, three (Srikuea & Hirunsai 2016). Furthermore, Vdr ablation main isoforms have been described in mouse (Dtna1, resulted in reduced grip strength and dysregulation of Dtna2, and Dtna3); however, slight rearrangements myogenic factors in mice mimicking atrophic phenotype within the internal exon usage in individual isoforms changes mainly attributed to reduced expression of genes generate multiple transcript variants encoding for the associated with calcium handling channels (Girgis et al. same isoform, further adding to the complexity of Dtna 2015). However, in the global VDRKO model, it is hard genomic region (Böhm et al. 2009). The largest isoform, to discriminate effects of direct VDR deletion in muscle DTNA1, is an 87 kDa protein (77–84 kDa in mouse) and those caused by mineral metabolism changes such originally discovered in postsynaptic membranes of as hypocalcaemia. Modifications in intracellular calcium Torpedo electric organ (Wagner et al. 1993), is enriched at levels by VD3 can be unavoidable even in conditional the neuromuscular junction, and possesses two syntrophin VDR null mice such as the myocyte-specific VDR knockout binding domains, a dystrophin/utrophin binding site mice described recently (Girgis et al. 2019) and interfere as well as a unique COOH-terminal containing three with muscle relaxation (Berchtold et al. 2000) or tamper potential tyrosine phosphorylation sites (Peters et al. with myoblast nature due to the disrupted regulation of 1998, Pawlikowski & Maimone 2009, Gingras et al. 2016). phosphate metabolism (Bellido & Boland 1987). It is thus DTNA2 exists in two alternative isoforms (DTNA2A and highly probable that the so-called VDR-muscle generated DTNA2B), possesses a unique C terminal domain, localizes effects observed previously are mediated by tissues other in the sarcolemma and the neuromuscular synapse, and than muscle or even by non-genomic mechanisms related binds only dystrophin (Enigk & Maimone 1999). The to the disrupted calcium uptake and thus are not a direct smallest DTNA3 isoform (42 kDa) contains two structural effect of muscle Vdr ablation per se. motifs belonging to the dystrophin-family proteins, lacks Dystrobrevin alpha (DTNA) is an essential structural the syntrophin binding domain (Ponting et al. 1996), component of the dystrophin associated protein complex and it is exclusively found in cardiac and skeletal muscle (DAPC). The DAPC maintains sarcolemmal stability during (Nawrotzki et al. 1998). The exact function of DTNA is muscle contraction and through its binding domains and unknown, but it has been speculated that, apart from its associated channel proteins aids signal transduction toward supportive role, it may aid in the transmission of DAPC muscle fibers to mainly protect them against damage from signaling (Newey et al. 2000). stress (Blake et al. 2002, Ehmsen et al. 2002). The core The identification of VDR in muscle tissue hints at the member of DAPC, dystrophin, serves as an anchor between presence of a direct pathway for VD3 to impact on skeletal the actin cytoskeleton and the connective tissue (Ervasti muscle function that is yet to be discovered. Herein, we & Campbell 1991, Petrof et al. 1993, Ohlendieck 1996). have shown that VD3 administration positively regulates Mutation on dystrophin gene leads to the X chromosome- Dtna gene and protein expression in C2C12 myogenic linked, progressive, fatal degenerative muscle disorder cells as well as in H2K-mdx52 that are immortalized cells called Duchenne muscular dystrophy (Hoffman et al. derived from the humanized mdx52 mouse model (Araki 1987). The C terminus of DTNA is strongly associated with et al. 1997). DTNA upregulation was strictly associated the C terminus of dystrophin through a specific coiled-coil with VDR expression levels in both healthy and https://jme.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/JME-19-0229 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 04:28:31AM via free access Journal of Molecular M K Tsoumpra et al. Upregulation of dystrobrevin by 64:3 197 Endocrinology calcitriol dystrophic myotubes. We have also identified a functional template for RT using
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