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.

. Continuous testosterone administration prevents skeletal muscle atrophy and enhances resistance to fatigue in orchidectomized male mice. Am J Physiol Endocrinol Metab 291: E506 -E516, 2006. First published April 18, 2006 doi:10.1152/ajpendo.00058.2006.-Androgens promote anabolism in skeletal muscle; however, effects on subsequent muscle function are less well defined because of a lack of reliable experimental models. We established a rigorous model of androgen withdrawal and administration in male mice and assessed androgen regulation of muscle mass, structure, and function. Adult C57Bl/6J male mice were orchidectomized (Orx) or sham-operated (Sham) and received 10 wk of continuous testosterone (T) or control treatment (C) via intraperitoneal implants. Mass, fiber cross-sectional area (CSA), and in vitro contractile function were assessed for fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. After 10 wk, OrxϩC mice had reduced body weight gain (P Ͻ 0.05), seminal vesicle mass (P Ͻ 0.01), and levator ani muscle mass (P Ͻ 0.001) compared with ShamϩC mice, and these effects were prevented with testosterone treatment. OrxϩT mice had greater EDL (P Ͻ 0.01) and SOL (P Ͻ 0.01) muscle mass compared with OrxϩC mice; however, median fiber CSA was not significantly altered in these muscles. EDL and SOL muscle force was greater in ShamϩT compared with OrxϩC mice (P Ͻ 0.05) in proportion to muscle mass. Unexpectedly, OrxϩT mice had increased fatigue resistance of SOL muscle compared with OrxϩC mice (P Ͻ 0.001). We used a rigorous model of androgen withdrawal and administration in male mice to demonstrate an essential role of androgens in the maintenance of muscle mass and force. In addition, we showed that testosterone treatment increases resistance to fatigue of slow-but not fast-twitch muscle. contractile function; force; androgen receptor RECENT WELL-CONTROLLED, double-blinded studies have demonstrated unequivocally that androgens regulate muscle mass in humans (29); however, the effect of androgens on subsequent muscle strength is less clear. Anecdotal evidence of muscle anabolism and enhanced physical performance in steroid-using athletes suggests that increased muscle bulk is explicitly linked to enhanced muscle function (66). To date, this premise remains unsubstantiated because of contradictory reports of the effect of androgens on muscle force-producing capacity in both human and animal studies.In humans, there is clear evidence that physiological testosterone administration increases lean body mass in conditions of low circulating androgens. Testosterone replacement therapy has been effectively used to counteract loss of lean body mass in hypogonadal men (4, 11, 32), older men with normal or low serum testosterone (21, 54), and human immunodeficiency virus (HIV)-infected men with low serum testosterone (2). Similarly, muscle anabolism has been achieved in eugonadal states following supraphysiological administration to young, healthy men (3, 25) and in HIV-infected men with normal ...

Androgen treatment can enhance the size and strength of muscle. However, the mechanisms of androgen action in skeletal muscle are poorly understood. This review discusses potential mechanisms by which androgens regulate satellite cell activation and function. Studies have demonstrated that androgen administration increases satellite cell numbers in animals and humans in a dose-dependent manner. Moreover, androgens increase androgen receptor levels in satellite cells. In vitro, the results are contradictory as to whether androgens regulate satellite cell proliferation or differentiation. IGF-I is one major target of androgen action in satellite cells. In addition, the possibility of non-genomic actions of androgens on satellite cells is discussed. In summary, this review focuses on exploring potential mechanisms through which androgens regulate satellite cells, by analyzing developments from research in this area.

In this study, we report that the transcription factor c-Maf is required for normal chondrocyte differentiation during endochondral bone development. c-maf is expressed in hypertrophic chondrocytes during fetal development (E14.5-E18.5), with maximal expression in the tibia occurring at E15.5 and E16.5, in terminally differentiated chondrocytes. In c-maf-null mice, fetal bone length is decreased approximately 10%, and hypertrophic chondrocyte differentiation is perturbed. There is an initial decrease in the number of mature hypertrophic chondrocytes at E15.5 in c-maf-null tibiae, with decreased expression domains of collagen X and osteopontin, markers of hypertrophic and terminal hypertrophic chondrocytes, respectively. By E16.5, there is an expanded domain of late hypertrophic, osteopontin-positive chondrocytes in the c-maf-/-. This accumulation of hypertrophic chondrocytes persists and is still observed at 4 weeks of age. These data suggest that c-Maf facilitates the initial chondrocyte terminal differentiation and influences the disappearance of hypertrophic chondrocytes. BrdU and TUNEL analyses show normal proliferation rate and apoptosis in the c-maf-null. There is a specific decrease in MMP-13 expression at E15.5 in the c-maf-null. MMP-13 is known to be regulated by AP-1 and may also be a target of c-Maf. Thus, cartilage is a novel system in which c-Maf acts during development, where c-Maf is required for normal chondrocyte differentiation.