Continuous testosterone administration prevents skeletal muscle atrophy and enhances resistance to fatigue in orchidectomized male mice

Abstract

. 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 ...

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

“…All mouse lines were back-crossed to a congenic C57BL/6 background (>10 generations back-cross), and control littermates (AR lox hemizygous males, cre heterozygous males and wildtype (WT) males) were used for both lines. We also analyzed gene expression in gastrocnemius muscle from our previously described global AR ΔZF2 and androgen deprivation models: WT and global AR ΔZF2 , 9 weeks of age, n ≥ 24, and WT C57BL/6 orchidectomized males treated ± testosterone for 10 weeks, 8 weeks of age, n ≥ 8 (Axell et al 2006, MacLean et al 2008b). Mice were housed in a conventional facility, and standard chow and water provided ad libitum.…”

“…Androgens are also required to increase muscle mass in adult males. Androgen withdrawal-dependent muscle atrophy has been demonstrated in both normal men and men with prostate cancer undergoing androgen ablation therapy (Mauras et al 1998, Basaria et al 2002, with a similar decrease in muscle mass occurring following orchidectomy in male mice (Axell et al 2006). Because testosterone levels decline in aging males, this may be one mechanism contributing to age-related sarcopenia.…”

Força muscular, níveis séricos de testosterona e de ureia em jogadores de futebol submetidos à periodização ondulatória

“…Increase in muscle mass depends on protein synthesis, being it influenced by the endogenous responses of the many anabolic hormones, among which, we highlight testosterone 3 . This hormone is necessary for maintenance of muscular mass and anabolism in humans, although it occurs by ways somehow not very clear yet, but it is important for the structure and function of the skeletal muscle 4 . Kuoringet al 5 observed increase of isometric strength and muscular mass of lower limbs, corroborating the interaction between endogenous testosteroneand androgenic receptors (AR) in the recovery phase, with consequent increase of protein synthesis, muscular hypertrophy and strength.…”

Supra-physiological doses of testosterone affect membrane oxidation of human neutrophils monitored by the fluorescent probe C11-BODIPY581/591

“…Since aging is regularly associated with a gradual decline in circulating testosterone concentrations and decreased musculature in men, AAS replacement therapies have been currently suggested to circumvent the age--related morbidity and cognitive impairment in men (Dillon et al2010). Accordingly, supra--physiologic (50 nM = 50--fold normal) dosing of testosterone for eight continuous weeks has been shown protective to muscle mass and fatigue resistance in orchiectomized mice compared to sham operated animals (Axell et al 2006). The protective action of testosterone on skeletal muscle and cognitive capacities may in part be due to its anti--inflammatory actions or through direct modulation of anti--catabolic pathways (Thompson et al 2006;Liva and Voskuhl 2001;Malkin et al 2004).…”