Physical activity in the androgen receptor knockout mouse: Evidence for reversal of androgen deficiency on cancellous bone

Ophoff, Jill; Callewaert, Filip; Venken, Katrien; Gendt, Karel De; Ohlsson, Claes; Gayan‐Ramirez, Ghislaine; Decramer, Marc; Boonen, Steven; Bouillon, Roger; Verhoeven, Guido; Vanderschueren, Dirk

doi:10.1016/j.bbrc.2008.11.016

Cited by 34 publications

(29 citation statements)

References 26 publications

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“…The estrogen-deficient aromatase knockout mouse model has increased abdominal fat and shows decreased spontaneous activity (25) but increased voluntary activity (23), demonstrating that these two types of activity can be regulated in an opposing manner. The decreased voluntary activity in our DBD-ARKO males is similar to that of the Verhoeven group's AR-null model (44), supporting the hypothesis that androgens act through the AR to increase voluntary activity. We have recently shown that male mice with muscle-specific AR deletion have a mild reduction in muscle mass but normal voluntary activity levels (unpublished data).…”

Section: Discussionsupporting

confidence: 78%

“…Muscle mass is reported to be unchanged in both these AR-null models (14, 31), unlike the decreased muscle mass in our DBD-ARKO model (35). In contrast, the Verhoeven ARnull model (exon 2 deletion, homogeneous C57BL/6 background) has a lower lean body mass but no change in fat mass between 5 and 16 wk, as determined by DEXA (44). Differences in the phenotype observed in our model compared with these other models that have late-onset obesity may arise through non-DNA binding-dependent actions of the AR or may be due to differences in the genetic background (31,48).…”

Section: Discussioncontrasting

confidence: 73%

“…Genetic background affects numerous trait characteristics, from body composition, bone mineral density, lipid levels, glucose levels, and hormone levels to activity (1,30,53). Of the three ARKO models already described, our model can be directly compared with the Verhoeven model (44), as both are on a C57BL/6 background. The lack of adiposity phenotype in the Verhoeven model could be due to the relative insensitivity of DEXA analysis to detect changes in specific fat depots vs. direct measurements of fat pad weight.…”

Section: Discussionmentioning

confidence: 98%

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Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Rana

Fam

Clarke

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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In men, as testosterone levels decrease, fat mass increases and muscle mass decreases. Increased fat mass in men, in particular central obesity, is a major risk factor for type 2 diabetes, cardiovascular disease, and all-cause mortality. Testosterone treatment has been shown to decrease fat mass and increase fat-free mass. We hypothesize that androgens act directly via the DNA binding-dependent actions of the androgen receptor (AR) to regulate genes controlling fat mass and metabolism. The aim of this study was to determine the effect of a global DNA binding-dependent (DBD) AR knockout (DBD-ARKO) on the metabolic phenotype in male mice by measuring body mass, fat mass, food intake, voluntary physical activity, resting energy expenditure, substrate oxidation rates, serum glucose, insulin, lipid, and hormone levels, and metabolic gene expression levels and second messenger protein levels. DBD-ARKO males have increased adiposity despite a decreased total body mass compared with wild-type (WT) males. DBD-ARKO males showed reduced voluntary activity, decreased food intake, increased serum leptin and adiponectin levels, an altered lipid metabolism gene profile, and increased phosphorylated CREB levels compared with WT males. This study demonstrates that androgens acting via the DNA binding-dependent actions of the AR regulate fat mass and metabolism in males and that the increased adiposity in DBD-ARKO male mice is associated with decreased voluntary activity, hyperleptinemia and hyperadiponectinemia and not with insulin resistance, increased food intake, or decreased resting energy expenditure.

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Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

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Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Rana

Fam

Clarke

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…This is in contrast to AR-null AR knockout (ARKO) models, which have very mild reductions in muscle mass (Ophoff et al 2009a). A myofiber-specific AR-null ARKO mouse model has little change in the mass of hind-limb muscles, similar to their global ARKO model, but a reduction in the mass of the highly androgen-sensitive perineal muscle, the levator ani (LA) (Ophoff et al 2009a,b, Pang et al 2011. A musclespecific ARKO mouse line with deletion of the AR in both myoblasts and myofibers also has no reduction in hind-limb muscle mass, but reduced LA muscle mass (Chambon et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Muscle-specific androgen receptor deletion shows limited actions in myoblasts but not in myofibers in different muscles in vivo

Rana¹,

Chiu²,

Russell³

et al. 2016

Journal of Molecular Endocrinology

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The aim of this study was to investigate the direct muscle cell-mediated actions of androgens by comparing two different mouse lines. The cre-loxP system was used to delete the DNA-binding activity of the androgen receptor (AR) in mature myofibers (MCK mAR ΔZF2 ) in one model and the DNA-binding activity of the AR in both proliferating myoblasts and myofibers (α-actin mAR ΔZF2 ) in another model. We found that hind-limb muscle mass was normal in MCK mAR ΔZF2 mice and that relative mass of only some hind-limb muscles was reduced in α-actin mAR ΔZF2 mice. This suggests that myoblasts and myofibers are not the major cellular targets mediating the anabolic actions of androgens on male muscle during growth and development. Levator ani muscle mass was decreased in both mouse lines, demonstrating that there is a myofiber-specific effect in this unique androgen-dependent muscle. We found that the pattern of expression of genes including c-myc, Fzd4 and Igf2 is associated with androgen-dependent changes in muscle mass; therefore, these genes are likely to be mediators of anabolic actions of androgens. Further research is required to identify the major targets of androgen actions in muscle, which are likely to include indirect actions via other tissues.

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“…Similarly, Chang et al [72] report an obese phenotype with enlarged gonadal and perirenal fat pads and larger adipocytes in their AR-null model. However, a third ARKO model shows a decreased muscle cross-sectional area accompanied by reduced potential of voluntary running but without increased adiposity or obesity [73,74]. Surprisingly, myocyte-specific AR knockout (mARKO) mice not only have a lower muscle mass but also a lower intra-abdominal fat mass [75].…”

Section: Pluripotent Muscle-adipose Progenitor Cellsmentioning

confidence: 99%

Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions

Dubois

Laurent

Boonen

et al. 2011

Cell. Mol. Life Sci.

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140

111

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Androgens increase both the size and strength of skeletal muscle via diverse mechanisms. The aim of this review is to discuss the different cellular targets of androgens in skeletal muscle as well as the respective androgen actions in these cells leading to changes in proliferation, myogenic differentiation, and protein metabolism. Androgens bind and activate a specific nuclear receptor which will directly affect the transcription of target genes. These genes encode muscle-specific transcription factors, enzymes, structural proteins, as well as microRNAs. In addition, anabolic action of androgens is partly established through crosstalk with other signaling molecules such as Akt, myostatin, IGF-I, and Notch. Finally, androgens may also exert non-genomic effects in muscle by increasing Ca(2+) uptake and modulating kinase activities. In conclusion, the anabolic effect of androgens on skeletal muscle is not only explained by activation of the myocyte androgen receptor but is also the combined result of many genomic and non-genomic actions.

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Physical activity in the androgen receptor knockout mouse: Evidence for reversal of androgen deficiency on cancellous bone

Cited by 34 publications

References 26 publications

Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Muscle-specific androgen receptor deletion shows limited actions in myoblasts but not in myofibers in different muscles in vivo

Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions

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