Impaired skeletal muscle development and function in male, but not female, genomic
            <i>androgen receptor</i>
            knockout mice

MacLean, Helen E.; Chiu, W.S. Maria; Notini, Amanda J.; Axell, Anna-Maree; Davey, Rachel A; McManus, J. F.; Ma, Cathy; Plant, David R.; Lynch, Gordon S.; Zajac, Jeffrey D

doi:10.1096/fj.08-105726

Cited by 179 publications

(221 citation statements)

References 45 publications

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“…3). This observation is in agreement with recent findings in ARKO mice where classic MRF genes were not regulated, and the overall gene profile suggested that androgens delay differentiation allowing clonal expansion of myoblasts (MacLean et al 2008). These data do not exclude the possibility that these genes are involved in androgenic anabolism, as they could be regulated in a small proportion of cells, by a post-transcriptional mechanism, or at later time points.…”

Section: Discussionsupporting

confidence: 88%

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Gentile¹,

Nantermet²,

Vogel³

et al. 2009

Journal of Molecular Endocrinology

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Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5a-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.

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Section: Discussionsupporting

confidence: 88%

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Gentile¹,

Nantermet²,

Vogel³

et al. 2009

Journal of Molecular Endocrinology

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“…Raldh1 , which encodes the RA synthetic enzyme retinaldehyde dehydrogenase 1 present in tanycytes (Shearer et al, 2010), was investigated as a gene regulated by several nuclear receptor family members (Fujiwara et al, 2009; Huq et al, 2006; MacLean et al, 2008). This gene was significantly upregulated in the hypothalamus of T3‐treated rats (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However despite considerable investigation, the genes directly regulated by TH in the hypothalamus are largely unknown; indeed, the genes regulated by TH in much of the brain remain undiscovered. Retinaldehyde dehydrogenase 1 (Raldh1, also known as Aldh1a1) is regulated by a number of hormone activators of nuclear receptors, such as estrogen (Fujiwara et al, 2009) and androgen (MacLean et al, 2008), as well as metabolite‐regulated nuclear receptors such as LXR (Huq et al, 2006). Via its synthesis of retinoic acid (RA) from retinaldehyde, Raldh1 itself then controls the activity of further nuclear receptors, the retinoic acid receptors (RARs).…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439

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“…We have previously shown that Global-ARKO mice have increased fat mass and decreased lean mass, resulting in an overall decrease in body weight. (21,38,42) Replacement of the AR in osteoblasts from either the proliferative or mineralization stage of their maturation in Global-ARKO mice further reduced their body weight such that body weight in the pOBL-and mOBL-AR gene replacement mice was lower compared with Global-ARKOs. This is in line with the reduced body weight we observed in the pOBLAR-tg and mOBLAR-tg mice after their backcrossing to a C57BL/6 background, before their use to generate the pOBL-and mOBL-AR gene replacement mice.…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

Russell

Clarke

Cheong

et al. 2014

Journal of Bone and Mineral Research

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Androgen action via the androgen receptor (AR) is essential for normal skeletal growth and bone maintenance post-puberty in males; however, the molecular and cellular mechanisms by which androgens exert their actions in osteoblasts remains relatively unexplored in vivo. To identify autonomous AR actions in osteoblasts independent of AR signaling in other tissues, we compared the extent to which the bone phenotype of the Global-ARKO mouse was restored by replacing the AR in osteoblasts commencing at either the 1) proliferative or 2) mineralization stage of their maturation. In trabecular bone, androgens stimulated trabecular bone accrual during growth via the AR in proliferating osteoblasts and maintained trabecular bone post-puberty via the AR in mineralizing osteoblasts, with its predominant action being to inhibit bone resorption by decreasing the ratio of receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) gene expression. During growth, replacement of the AR in proliferating but not mineralizing osteoblasts of Global-ARKOs was able to partially restore periosteal circumference, supporting the concept that androgen action in cortical bone to increase bone size during growth is mediated via the AR in proliferating osteoblasts. This study provides further significant insight into the mechanism of androgen action via the AR in osteoblasts, demonstrating that it is dependent on the stage of osteoblast maturation.

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Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice

Cited by 179 publications

References 45 publications

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

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