Selective Androgen Receptor Modulator, YK11, Regulates Myogenic Differentiation of C2C12 Myoblasts by Follistatin Expression

Kanno, Yuichiro; Ota, Rumi; Someya, Kousuke; Kusakabe, Taichi; Kato, Kanefusa; Inouye, Yoshio

doi:10.1248/bpb.b13-00231

Cited by 26 publications

(22 citation statements)

References 37 publications

(37 reference statements)

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“…This compound has a partial agonistic effect on AR compared to dihydrotestosterone (DHT) as determined by a reporter gene assay. 24) Furthermore, we found that YK11 accelerates myogenic differentiation in C2C12 myoblast cells. 25) The present study focus on the bone anabolic effect of YK11 on osteoblastic differentiation.…”

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confidence: 70%

Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells

Yatsu

Kusakabe

Kato

et al. 2018

Biological & Pharmaceutical Bulletin

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Androgens are key regulators that play a critical role in the male reproductive system and have anabolic effects on bone mineral density and skeletal muscle mass. We have previously reported that YK11 is a novel selective androgen receptor modulator (SARM) and induces myogenic differentiation and selective gene regulation. In this study, we show that treatment of YK11 and dihydrotestosterone (DHT) accelerated cell proliferation and mineralization in MC3T3-E1 mouse osteoblast cells. Further, YK11-treated cells increased osteoblast specific differentiation markers, such as osteoprotegerin and osteocalcin, compared to untreated cells. These observations were attenuated by androgen receptor (AR) antagonist treatment. To clarify the effect of YK11, we investigated rapid non-genomic signaling by AR. The phosphorylated Akt protein level was increased by YK11 and DHT treatment, suggesting that YK11 activates Akt-signaling via non-genomic signaling of AR. Because it is known Akt-signaling is a key regulator of androgen-mediated osteoblast differentiation, YK11 has osteogenic activity as well as androgen.

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confidence: 70%

Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells

Yatsu

Kusakabe

Kato

et al. 2018

Biological & Pharmaceutical Bulletin

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“…In mouse and chick, FST functions as a positive regulator of muscle development and growth by inhibiting TGF-␤ family members including myostatin (2,23,34,43,64). As to cellular behavior, FST regulates the proliferation (4,7,23,35), differentiation (4,32), and fusion (29) of muscle cells in myogenesis in vivo and in vitro of mouse and duck. The present evidence (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of the crucial molecular events during the large-scale myoblast fusion in sheep

Wei

et al. 2014

Physiological Genomics

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It is well known that in sheep most myofibers are formed before birth; however, the crucial myogenic stage and the cellular and molecular mechanisms underpinning phenotypic variation of fetal muscle development remain to be ascertained. We used histological, microarray, and quantitative realtime PCR (qPCR) methods to examine the developmental characteristics of fetal muscle at 70, 85, 100, 120, and 135 days of gestation in sheep. We show that day 100 is an important checkpoint for change in muscle transcriptome and histomorphology in fetal sheep and that the period of 85-100 days is the vital developmental stage for large-scale myoblast fusion. Furthermore, we identified the cisregulatory motifs for E2F1 or MEF2A in a list of decreasingly or increasingly expressed genes between 85 and 100 days, respectively. Further analysis demonstrated that the mRNA and phosphorylated protein levels of E2F1 and MEF2A significantly declined with myogenic progression in vivo and in vitro. qRT-PCR analysis indicated that PI3K and FST, as targets of E2F1, may be involved in myoblast differentiation and fusion and that downregulation of MEF2A contributes to transition of myofiber types by differential regulation of the target genes involved at the stage of 85-100 days. We clarify for the first time the timing of myofiber proliferation and development during gestation in sheep, which would be beneficial to meat sheep production. Our findings present a repertoire of gene expression in muscle during large-scale myoblast fusion at transcriptome-wide level, which contributes to elucidate the regulatory network of myogenic differentiation.sheep; muscle; cis-regulatory motif; histology; microarray UNLIKE THE SMALL MAMMALS with two myogenic waves during development, there are at least three generations of myotubes in sheep (63). Myofiber formation in the sheep fetus begins at ϳ32 days of gestation, and the full complement of myofibers is achieved by days 80 -120 of gestation (3,39). Previous studies provide the valuable information on association between gene expression and prenatal skeletal muscle development in sheep at transcriptome-wide level (10,50,62). However, to our best knowledge, we still do not know the specific developmental stage at which large-scale fetal myoblasts undergo differentiation and fusion in sheep, or the ongoing molecular mechanisms underpinning the phenotypic variations in muscle during the fetal period.Myogenesis is a multiple-step process, including cell determination, proliferation, differentiation, and fusion, that is orchestrated by the expression of a cascade of transcriptional regulators such as Pax3/Pax7, members of the MyoD, MEF2, and E2F family, and so on (9, 44, 59). Myoblast fusion is a critical process that contributes to the growth of muscle during development and to the regeneration of myofibers upon injury. Myoblasts fuse with each other as well as with multinucleated myotubes to enlarge the myofiber. At the cellular level, the fusion process is characterized by the alignment of myoblast and myotu...

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“…The expression of neither IGF-1 isoform, however, was significantly impacted by tumor or treatment (Supplemental Figure 5). Myostatin signaling also governs skeletal muscle mass and is another target of androgens as myostatin, its receptor ACVRIIB, and the negative regulator of myostatin, follistatin, have all been shown to be androgen-regulated [35,53,54]. ACVRIIB was induced by the presence of C-26 tumors and was significantly suppressed only by AR-42 treatment, alone or in combination with GTx-024 ( Figure 4D).…”

Section: Impact Of Gtx-024 and Ar-42 Administration On Androgen Recepmentioning

confidence: 98%

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

Tseng

Liva

Dauki

et al. 2017

Preprint

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BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

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Selective Androgen Receptor Modulator, YK11, Regulates Myogenic Differentiation of C2C12 Myoblasts by Follistatin Expression

Cited by 26 publications

References 37 publications

Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells

Selective Androgen Receptor Modulator, YK11, Up-Regulates Osteoblastic Proliferation and Differentiation in MC3T3-E1 Cells

Identification of the crucial molecular events during the large-scale myoblast fusion in sheep

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

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