Testosterone Signals through mTOR and Androgen Receptor to Induce Muscle Hypertrophy

Basualto-Alarcón, Carla; Jorquera, Gonzalo; Altamirano, Francisco; Jaimovich, Enrique; Estrada, Manuel

doi:10.1249/mss.0b013e31828cf5f3

Cited by 116 publications

(100 citation statements)

References 36 publications

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“…In this study, the protein level of Akt phosphorylation was observed as early as 5 min after AS treatment and reached maximum protein expression at 15 min. These results were consistent with previous reports [30]. …”

Section: Discussionsupporting

confidence: 94%

“…Phosphorylation of Ser 473 is required for maximal activation of Akt and it appears that Akt might have a relatively short activation period after nutritional stimulation is activated by protein growth factors [30-32]. In this study, the protein level of Akt phosphorylation was observed as early as 5 min after AS treatment and reached maximum protein expression at 15 min.…”

Section: Discussionmentioning

confidence: 50%

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Angelica Sinensis promotes myotube hypertrophy through the PI3K/Akt/mTOR pathway

Yeh

Hsu

Yang

et al. 2014

BMC Complement Altern Med

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BackgroundAngelica Sinensis (AS), a folk medicine, has long been used in ergogenic aids for athletes, but there is little scientific evidence supporting its effects. We investigated whether AS induces hypertrophy in myotubes through the phosphatidylinositol 3-kinase (PI3K)/Akt (also termed PKB)/mammalian target of the rapamycin (mTOR) pathway.MethodsAn in vitro experiment investigating the induction of hypertrophy in myotubes was conducted. To investigate whether AS promoted the hypertrophy of myotubes, an established in vitro model of myotube hypertrophy with and without AS was used and examined using microscopic images. The role of the PI3K/Akt/mTOR signaling pathway in AS-induced myotube hypertrophy was evaluated. Two inhibitors, wortmannin (an inhibitor of PI3K) and rapamycin (an inhibitor of mTOR), were used.ResultThe results revealed that the myotube diameters in the AS-treated group were significantly larger than those in the untreated control group (P < 0.05). Wortmannin and rapamycin inhibited AS-induced hypertrophy. Furthermore, AS increased Akt and mTOR phosphorylation through the PI3K pathway and induced myotube hypertrophy.ConclusionThe results confirmed that AS induces hypertrophy in myotubes through the PI3K/Akt/mTOR pathway.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 50%

Angelica Sinensis promotes myotube hypertrophy through the PI3K/Akt/mTOR pathway

Yeh

Hsu

Yang

et al. 2014

BMC Complement Altern Med

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“…They demonstrated that podocytes express both androgen and estrogen receptors and that in vitro, testosterone can cause podocyte apoptosis, which is blocked by the addition of flutamide (18). In skeletal and cardiac muscle cells, testosterone signals through the mammalian target of rapamycin pathway (19,20). Likewise, the importance of mammalian target of rapamycin signaling in podocytes and in essential podocyte functions, including autophagy (21) and compensatory hypertrophy (22), is increasingly recognized.…”

Section: Pathogenesis Of Aas-associated Renal Injurymentioning

confidence: 99%

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Pendergraft

Herlitz

Thornley‐Brown

et al. 2014

Clinical Journal of the American Society of Nephrology

101

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The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue-like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCAassociated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves.

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“…5A). Intriguingly, relative mRNA levels of several factors associated with muscle anabolism, notably IGF1 and androgen receptor (AR) (33,34), were increased in MT-null mice. In addition, the mRNA levels of myogenin and ornithine decarboxylase (Odc1), which has previously been shown to regulate myoblast proliferation (35), were significantly elevated in the absence of metallothioneins.…”

Section: Resultsmentioning

confidence: 99%

Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

Summermatter

Bouzan

Pierrel

et al. 2017

Molecular and Cellular Biology

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Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.KEYWORDS muscle metabolism S keletal muscle hypertrophy is characterized in the adult mammal by an increase in the size of preexisting myofibers. The induction of hypertrophy involves an activation of the pathways that increase protein synthesis and inhibition of cellular signaling, which induces protein degradation. Hypertrophy can be induced by the activation of Akt, through multiple potential inputs (1). Akt induces hypertrophy in part by activating the mTOR/70S6 kinase pathway. In addition, Akt inhibits protein degradation, by phosphorylating and therefore blocking Foxo1 and Foxo3-transcription factors which are required for the upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, which help mediate protein turnover during muscle atrophy (2-4). Therefore, activation of Akt constitutes a critical signaling node to increase muscle hypertrophy and block muscle atrophy (1).Mammalian metallothioneins (MTs) belong to a family of cysteine-rich, metalbinding proteins. In rodents, four MT isoforms have been identified: the two major isoforms, MT-1 and MT-2, are ubiquitously expressed, while MT-3 and MT-4 show tissue specific expression in the central nervous system and squamous epithelia, respectively. In humans, multiple isoforms have been reported for MT-1 (MT-1A, MT-1B, MT-1E, MT-1F, MT-1G, MT-1H, MT-1M, and MT-1X), while no splice variants are documented for MT-2, MT-3, or MT-4 (5; for a review, see reference 6).MTs play a role in cellular zinc homeostasis, mitochondrial function (7), defense against oxidative stress (8), and defense against inflammation (5). Moreover, several reports and a recent review highlight a role of metallothioneins in cancer (9), aging (10), and the onset of particular central nervous system diseases (11).

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Testosterone Signals through mTOR and Androgen Receptor to Induce Muscle Hypertrophy

Abstract: These results suggest a crosstalk between pathways involving fast intracellular signaling and the AR to explain testosterone-induced skeletal muscle hypertrophy.

Cited by 116 publications

References 36 publications

Angelica Sinensis promotes myotube hypertrophy through the PI3K/Akt/mTOR pathway

Angelica Sinensis promotes myotube hypertrophy through the PI3K/Akt/mTOR pathway

Nephrotoxic Effects of Common and Emerging Drugs of Abuse

Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

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