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

Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
The FASEB Journal (Impact Factor: 5.04). 05/2008; 22(8):2676-89. DOI: 10.1096/fj.08-105726
Source: PubMed


To identify mechanisms of anabolic androgen action in muscle, we generated male and female genomic androgen receptor (AR) knockout (ARKO) mice, and characterized muscle mass, contractile function, and gene expression. Muscle mass is decreased in ARKO males, but normal in ARKO females. The levator ani muscle, which fails to develop in normal females, is also absent in ARKO males. Force production is decreased from fast-twitch ARKO male muscle, and slow-twitch muscle has increased fatigue resistance. Microarray analysis shows up-regulation of genes encoding slow-twitch muscle contractile proteins. Real-time PCR confirms that expression of genes encoding polyamine biosynthetic enzymes, ornithine decarboxylase (Odc1), and S-adenosylmethionine decarboxylase (Amd1), is reduced in ARKO muscle, suggesting androgens act through regulation of polyamine biosynthesis. Altered expression of regulators of myoblast progression from proliferation to terminal differentiation suggests androgens also promote muscle growth by maintaining myoblasts in the proliferate state and delaying differentiation (increased Cdkn1c and Igf2, decreased Itg1bp3). A similar pattern of gene expression is observed in orchidectomized male mice, during androgen withdrawal-dependent muscle atrophy. In conclusion, androgens are not required for peak muscle mass in females. In males, androgens act through the AR to regulate multiple gene pathways that control muscle mass, strength, and fatigue resistance.

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Available from: Helen Maclean, Aug 21, 2014
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    • "Despite the presence of T3 in the hypothalamus, no significant changes in the expression of agouti-related protein (Agrp), growth hormone-releasing hormone (Ghrh), neuropeptide Y (Npy), cocaine-and amphetamineregulated transcript (Cart) or proopiomelanocortin (Pomc) were observed in T3-treated animals after 4 hours (Fig. 1A). 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. 1A). "
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    ABSTRACT: 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 2015.
    Glia 11/2015; DOI:10.1002/glia.22938 · 6.03 Impact Factor
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    • "of genes encoding muscle contractile proteins (MacLean et al., 2008; Yoshioka et al., 2007). "
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    ABSTRACT: MicroRNAs (miRNAs) are important modulators of skeletal muscle development in multiple mammalian species, but their role in skeletal muscle growth in castrated male pigs has not been well studied. The aim of the present study was to determine the role of miRNAs in longissimus dorsi muscle under castration. Our results showed that castration caused a significant decrease in serum testosterone levels as well as carcass lean mass, but led to an increase in carcass fat mass. Moreover, miRNA expression profiles in skeletal muscle were significantly altered by castration, and seven differentially expressed miRNAs were discovered. More importantly, functional analysis suggested that these differentially expressed miRNAs and their targets are involved in the regulation of skeletal muscle contractile function and fat metabolism. Taken together, these results demonstrate altered miRNA expression in skeletal muscle of castrated male pigs, and suggest a potential mechanism underlying the effects of castration on porcine skeletal muscle growth.
    Research in Veterinary Science 12/2014; 99. DOI:10.1016/j.rvsc.2014.12.012 · 1.41 Impact Factor
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    • "In addition, myofibril organization was found to be disrupted in muscle-specific AR-deficient mice [55, 56]. On the other hand, McLean and coworkers reported the characterization of AR total knock-out mice [57]. Male ARKO mice displayed a significantly reduced skeletal mass which could not be linked to a modulation of IGF-1 signaling [57]. "
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    ABSTRACT: Background Muscle wasting is a hallmark of many chronic conditions but also of aging and results in a progressive functional decline leading ultimately to disability. Androgens, such as testosterone were proposed as therapy to counteract muscle atrophy. However, this treatment is associated with potential cardiovascular and prostate cancer risks and therefore not acceptable for long-term treatment. Selective Androgen receptor modulators (SARM) are androgen receptor ligands that induce muscle anabolism while having reduced effects in reproductive tissues. Therefore, they represent an alternative to testosterone therapy. Our objective was to demonstrate the activity of SARM molecule (GLPG0492) on a immobilization muscle atrophy mouse model as compared to testosterone propionate (TP) and to identify putative biomarkers in the plasma compartment that might be related to muscle function and potentially translated into the clinical space. Methods GLPG0492, a non-steroidal SARM, was evaluated and compared to TP in a mouse model of hindlimb immobilization. Results GLPG0492 treatment partially prevents immobilization-induced muscle atrophy with a trend to promote muscle fiber hypertrophy in a dose-dependent manner. Interestingly, GLPG0492 was found as efficacious as TP at reducing muscle loss while sparing reproductive tissues. Furthermore, gene expression studies performed on tibialis samples revealed that both GLPG0492 and TP were slowing down muscle loss by negatively interfering with major signaling pathways controlling muscle mass homeostasis. Finally, metabolomic profiling experiments using 1H-NMR led to the identification of a plasma GLPG0492 signature linked to the modulation of cellular bioenergetic processes. Conclusions Taken together, these results unveil the potential of GLPG0492, a non-steroidal SARM, as treatment for, at least, musculo-skeletal atrophy consecutive to coma, paralysis, or limb immobilization.
    BMC Musculoskeletal Disorders 09/2014; 15(1):291. DOI:10.1186/1471-2474-15-291 · 1.72 Impact Factor
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