Androgen receptor antagonist suppresses exercise-induced hypertrophy of skeletal muscle

Inoue, Kazuo; Yamasaki, Sho; Fushiki, Tohru; Okada, Yoshimune; Sugimoto, Etsuro

doi:10.1007/bf00867933

Cited by 96 publications

(61 citation statements)

References 14 publications

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“…Increased androgen receptor abundance could serve to increase the muscles' sensitivity to androgens. Androgen receptor induction may play an important role in overload-induced growth, because inhibition of androgen receptor action can partially attenuate overload-induced muscle growth in rats (26). However, the present data also support the hypothesis that androgen receptor induction is not sufficient for inducing muscle growth.…”

Section: Discussionsupporting

confidence: 72%

Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate

Lee

McClung

Hand

et al. 2003

Journal of Applied Physiology

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Lee, Won Jun, Joseph McClung, G. A. Hand, and James A. Carson. Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate. J Appl Physiol 94: 1153-1161, 2003; 10.1152/japplphysiol. 00822.2002.-This study's purpose was to examine whether functional overload with nandrolone decanoate (ND) administration increased muscle mass and steroid receptor concentration in aged rat soleus (Sol) and plantaris (Plan) muscle. ND (6 mg/kg body wt) was administered once a week for 4 wk, whereas control rats received sesame seed oil injections. Functional overload of the hindlimb Sol and Plan was induced by synergistic gastrocnemius muscle ablation at the beginning of the fourth week. Adult (5 mo of age) and aged rats (25 mo of age) were randomly assigned to four groups: control, overload, control-ND, and overload-ND. Seven days of functional overload increased adult Sol muscle mass 27%, whereas the aged Sol muscle mass did not change. The aged overloaded Sol muscle receiving ND significantly increased muscle weight by 35% and total muscle protein by 24%. Aged Plan muscle did not increase muscle weight with overload or ND treatment. Androgen receptor protein was induced by ND treatment and functional Ov, and combining the two treatments induced Sol androgen receptor protein concentration above either alone. Sol glucocorticoid receptor protein concentration increased in overload groups of both ages. ND administration can increase aged Sol muscle mass and protein content after 7 days of functional overload, and the cooperative induction of androgen receptor may be important for this response.

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Section: Discussionsupporting

confidence: 72%

Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate

Lee

McClung

Hand

et al. 2003

Journal of Applied Physiology

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“…This inhibitor has been used in cancer research in breast or prostate cancer (Bhattacharyya et al 2006, Auricchio et al 2008. Moreover, sex hormone receptor inhibitors have been used to investigate the molecular mechanism of sex hormone action in skeletal muscle (Inoue et al 1994). Interestingly, we show that the positive effect of testosterone on palmitate oxidation was abolished at the presence of the AR antagonist (CDX).…”

Section: Discussionmentioning

confidence: 87%

Testosterone or 17β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes

Salehzadeh¹,

Rune²,

Osler³

et al. 2011

Journal of Endocrinology

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Changes in sex hormone levels with aging or illness may lead to metabolic disorders. Moreover, the ratio changes in men versus women may have distinct pathological responses. Since little is known about sex hormone action on muscle metabolism, we examined the role of testosterone or 17b-estradiol (E 2 ) in metabolism and investigated whether either hormone may mediate a sex-specific effect. Myotubes from postmenopausal women and age-matched male donors were treated with 10 nM testosterone or E 2 for 4 days, and assays were performed to measure metabolic readouts, signal transduction, and mRNA expression. Testosterone and E 2 treatment enhanced insulin-stimulated glucose incorporation into glycogen and AKT phosphorylation in myotubes from female donors, highlighting a sexspecific role of sex hormone in glucose metabolism. Testosterone treatment increased palmitate oxidation in myotubes from both female and male donors, while E 2 enhanced palmitate oxidation in myotubes from male donors only. Testosterone-mediated increase in palmitate oxidation was attenuated at the presence of androgen receptor antagonist, which may indicate a role of nuclear steroid receptor in muscle lipid oxidation. Testosterone treatment increased mRNA expression of the insulin receptor substrate 2 in myotubes from male and female donors, whereas it increased mRNA expression of glycogen synthase 1 only in myotubes from male donors. E 2 treatment increased pyruvate dehydrogenase kinase 4 mRNA expression in myotubes from female donors. Thus, our data suggest that testosterone or E 2 modulates muscle glucose and lipid metabolism and may play a role in metabolism in a sex-dependent manner.

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“…Previously Joubert and Tobin (56) demonstrated that testosterone treatment of rat levator ani muscle resulted in activation of quiescent satellite cells, and increased replication and the fusion of satellite cells with myofibers. In the rodent, the role of AR in exercise-induced muscle growth was proven (57), as antiandrogen significantly reduced skeletal muscle gain.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of the Androgen Receptor via Serum Response Factor Facilitates Expression of a Myogenic Gene

Vlahopoulos

Zimmer

Jenster

et al. 2005

Journal of Biological Chemistry

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Androgen receptor (AR) induced precocious myogenesis in culture and myogenic specified gene activity. Increased levels of AR expression in replicating C2C12 myoblasts stimulated fusion into post-differentiated multinucleated myotubes and the appearance of skeletal ␣-actin transcripts, even in the absence of ligand. Furthermore, AR activated the skeletal ␣-actin promoter, which lacks GRE sites, in co-transfected C2C12 cells. AR co-activation of the skeletal ␣-actin promoter required co-expressed full-length serum response factor (SRF). In vitro, AR associated with SRF and was recruited by SRF to a ␣-actin promoter SRF binding site. Our data suggest that AR is capable of activating myogenic genes devoid of consensus AR binding sites via its recruitment by the myogenic enriched transcription factor, SRF.Steroid androgens play an important role in determining lean body mass and muscle strength. For example, men made hypogonadal lose lean body mass and muscle strength (1), whereas in older men, decrements in circulating testosterone levels correlates well with reduced musculature (2). In addition, treatment of hypogonadal men or older men with androgens elicited increased muscle strength and lean body mass (3, 4). Androgens used by healthy young athletes and weightlifters (5) maximize muscle mass and strength. Testosterone increased maximal voluntary strength in a dose-dependent manner (6, 7) and was shown to be a limiting factor in muscle strength development (8), during training-induced muscle hypertrophy (9). Androgens used as a treatment for cachexia also increased fat-free muscle mass and maximum voluntary strength (10). Thus, there is strong evidence that androgens increase muscle mass and strength, both under pathological and physiological conditions.Most studies conducted to date have focused on the positive role of androgens on skeletal muscle protein synthesis (11-13).The molecular basis of myogenic enhancement by androgens is not well understood (6,7,14). The androgen receptor (AR) 1 (15) is a member of the zinc finger class of transcription regulators, and the steroid and thyroid hormone receptor superfamily (16). AR binds androgens by a discrete domain at the 250 C-terminal amino acids of the primary structure (17, 18) and upon binding undergoes phosphorylation (19) and a conformational change. Proteins with the capacity to retain the receptor in the cytoplasm are dissociated and AR nuclear localization signals become exposed allowing for nuclear entry and transcription activation (20). Nuclear hormone receptors are divided in two families, in regard to the DNA sequences they recognize. Estrogen, thyroid, and retinoid acid receptors recognize estrogen response element-like (AGGTCA) sequences, whereas androgen, glucocorticoid, and progesterone receptors recognize GRElike (AGAACA) sequences (21-23). To date, there are no known direct AR DNA targets that drive myogenic specified genes (6). AR, as well as other members of the nuclear receptor superfamily, is modulated by coregulatory proteins (24). Steroid r...

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Androgen receptor antagonist suppresses exercise-induced hypertrophy of skeletal muscle

Cited by 96 publications

References 14 publications

Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate

Overload-induced androgen receptor expression in the aged rat hindlimb receiving nandrolone decanoate

Testosterone or 17β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes

Recruitment of the Androgen Receptor via Serum Response Factor Facilitates Expression of a Myogenic Gene

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