Testosterone represses ubiquitin ligases atrogin-1 and Murf-1 expression in an androgen-sensitive rat skeletal muscle in vivo

Pires-Oliveira, Marcelo; Maragno, Ana Leticia; Parreiras-e-Silva, Lucas T.; Chiavegatti, Tiago; Gomes, Marcelo D.; Godinho, Rosely Oliveira

doi:10.1152/japplphysiol.00490.2009

Cited by 50 publications

(30 citation statements)

References 64 publications

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“…Testosterone is known to suppress the ubiquitin ligase‐mediated atrophy pathway to preserve muscle mass 34, 37, 38, 39. Here again, our results support the idea that urolithin B mimics the effects of testosterone as it decreased the mRNA of the muscle‐specific ligases MuRF1 and MAFbx and the level of ubiquitinated proteins both in vitro and in denervated muscles.…”

Section: Discussionsupporting

confidence: 84%

Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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BackgroundThe control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin‐derived metabolite, on skeletal muscle growth.MethodsC2C12 myotubes were treated with 15 μM of urolithin B for 24 h. For in vivo experiments, mice were implanted with mini‐osmotic pumps delivering continuously 10 μg/day of urolithin B during 28 days. Muscle atrophy was studied in mice with a sciatic nerve denervation receiving urolithin B by the same way.ResultsOur experiments reveal that urolithin B enhances the growth and differentiation of C2C12 myotubes by increasing protein synthesis and repressing the ubiquitin–proteasome pathway. Genetic and pharmacological arguments support an implication of the androgen receptor. Signalling analyses suggest a crosstalk between the androgen receptor and the mTORC1 pathway, possibly via AMPK. In vivo experiments confirm that urolithin B induces muscle hypertrophy in mice and reduces muscle atrophy after the sciatic nerve section.ConclusionsThis study highlights the potential usefulness of urolithin B for the treatment of muscle mass loss associated with various (pathological) physiological states.

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Section: Discussionsupporting

confidence: 84%

Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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“…In a recent study done by Pires-Oliveira et al (2010), Fbxo32 expression was high in rat m. levator ani over a week after castration, and this increase could be reversed by treatment with testosterone. Interestingly, in another recent study done by Rogers et al (2010), mice showed decreased expression of Fbxo32 12 weeks after castration similar to what was observed in our study.…”

Section: Regulated Genes In Common For Dht and Ementioning

confidence: 87%

Stimulation of both estrogen and androgen receptors maintains skeletal muscle mass in gonadectomized male mice but mainly via different pathways

Svensson¹,

Movérare‐Skrtic²,

Windahl³

et al. 2010

Journal of Molecular Endocrinology

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Testosterone is a major regulator of muscle mass. Little is known whether this is due to a direct stimulation of the androgen receptor (AR) or mediated by aromatization of testosterone to estradiol (E 2 ), the ligand for the estrogen receptors (ERs), in peripheral tissues. In this study, we differentiated between the effects mediated by AR and ER by treating orchidectomized (orx) male mice for 5 weeks with E 2 or the non-aromatizable androgen dihydrotestosterone (DHT). Both E 2 and DHT increased muscle weight and lean mass, although the effect was less marked after E 2 treatment. Studies of underlying mechanisms were performed using gene transcript profiling (microarray and real-time PCR) in skeletal muscle, and they demonstrated that E 2 regulated 51 genes and DHT regulated 187 genes, with 13 genes (Z25% of E 2 -regulated genes) being regulated by both treatments. Both E 2 and DHT altered the expression of Fbxo32, a gene involved in skeletal muscle atrophy, affected the IGF1 system, and regulated genes involved in angiogenesis and the glutathione metabolic process. Only E 2 affected genes that regulate intermediary glucose and lipid metabolism, and only DHT increased the expression of genes involved in synaptic transmission and heme and polyamine biosynthesis. In summary, ER activation by E 2 treatment maintains skeletal muscle mass after orx. This effect is less marked than that of AR activation by DHT treatment, which completely prevented the effect of orx on muscle mass and was partly, but not fully, mediated via alternative pathways.

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“…Although we did not see any changes in Fbxo32 expression in vivo , expression of Fbxo32 was repressed by DHT in myoblasts in vitro . Other orchidectomy studies have shown upregulation of Fbxo32 expression in muscle,1351 with increased muscle protein degradation during atrophy,52 while androgen treatment increases muscle protein synthesis 53. Therefore, it is possible that androgen withdrawal-dependent atrophy occurs in part via the same myogenin-dependent ubiquitin ligase pathways activated in neurogenic atrophy, due to the loss of myogenin and Fbxo32 repression by the AR.…”

Section: Discussionmentioning

confidence: 99%

Expression of androgen receptor target genes in skeletal muscle

Rana¹,

Lee²,

Zajac³

et al. 2014

Asian J Androl

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We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (ARΔZF2) versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in ARΔZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7, p57Kip2, Igf2 and calcineurin Aa, was increased in ARΔZF2 muscle, and the expression of all but p57Kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

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Testosterone represses ubiquitin ligases atrogin-1 and Murf-1 expression in an androgen-sensitive rat skeletal muscle in vivo

Cited by 50 publications

References 64 publications

Urolithin B, a newly identified regulator of skeletal muscle mass

Urolithin B, a newly identified regulator of skeletal muscle mass

Stimulation of both estrogen and androgen receptors maintains skeletal muscle mass in gonadectomized male mice but mainly via different pathways

Expression of androgen receptor target genes in skeletal muscle

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