Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle

James P. White, Song Gao, Melissa J. Puppa, Shuichi Sato, Stephen L. Welle, James Carson

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42days or castrated and treated with the nandrolone decanoate (ND) (6mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling. In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C2C12 myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt.

Original languageEnglish (US)
Pages (from-to)174-186
Number of pages13
JournalMolecular and Cellular Endocrinology
Volume365
Issue number2
DOIs
StatePublished - Jan 3 2013

Fingerprint

Muscle
Testosterone
Skeletal Muscle
Skeletal Muscle Fibers
Phosphorylation
Muscles
Androgens
AMP-Activated Protein Kinases
Muscle Proteins
Chemical activation
Insulin-Like Growth Factor I
Proteins
Testosterone Congeners
TOR Serine-Threonine Kinases
mechanistic target of rapamycin complex 1
Raptors
Wasting Syndrome
Hypogonadism
Hand Strength
Inbred C57BL Mouse

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. / White, James P.; Gao, Song; Puppa, Melissa J.; Sato, Shuichi; Welle, Stephen L.; Carson, James.

In: Molecular and Cellular Endocrinology, Vol. 365, No. 2, 03.01.2013, p. 174-186.

Research output: Contribution to journalArticle

White, James P. ; Gao, Song ; Puppa, Melissa J. ; Sato, Shuichi ; Welle, Stephen L. ; Carson, James. / Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. In: Molecular and Cellular Endocrinology. 2013 ; Vol. 365, No. 2. pp. 174-186.
@article{f5743cc3b31e41ee963ec69b047e19b4,
title = "Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle",
abstract = "Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42days or castrated and treated with the nandrolone decanoate (ND) (6mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling. In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C2C12 myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt.",
author = "White, {James P.} and Song Gao and Puppa, {Melissa J.} and Shuichi Sato and Welle, {Stephen L.} and James Carson",
year = "2013",
month = "1",
day = "3",
doi = "10.1016/j.mce.2012.10.019",
language = "English (US)",
volume = "365",
pages = "174--186",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
number = "2",

}

TY - JOUR

T1 - Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle

AU - White, James P.

AU - Gao, Song

AU - Puppa, Melissa J.

AU - Sato, Shuichi

AU - Welle, Stephen L.

AU - Carson, James

PY - 2013/1/3

Y1 - 2013/1/3

N2 - Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42days or castrated and treated with the nandrolone decanoate (ND) (6mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling. In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C2C12 myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt.

AB - Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation. Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C2C12 myotubes. C57BL/6 mice were either castrated for 42days or castrated and treated with the nandrolone decanoate (ND) (6mg/kg bw/wk). Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3β, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets. Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C2C12 myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling. In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C2C12 myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt.

UR - http://www.scopus.com/inward/record.url?scp=84871362372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84871362372&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2012.10.019

DO - 10.1016/j.mce.2012.10.019

M3 - Article

VL - 365

SP - 174

EP - 186

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

IS - 2

ER -