Dihydrotestosterone stimulates amino acid uptake and the expression of LAT2 in mouse skeletal muscle fibres through an ERK1/2-dependent mechanism

J Physiol. 2011 Jul 15;589(Pt 14):3623-40. doi: 10.1113/jphysiol.2011.207175. Epub 2011 May 23.

Abstract

Dihydrotestosterone (DHT) has acute/non-genomic actions in adult mammalian skeletal muscles whose physiological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the acute/non-genomic effects of DHT on amino acid uptake as well as the cellular signal transduction events underlying these actions in mouse fast- and slow-twitch skeletal muscle fibre bundles. 14C-Labelled amino acids were used to investigate the effects of DHT and testosterone (T) on amino acid uptake and pharmacological interventions were used to determine the cellular signal transduction events mediating these actions. While T had no effect on the uptake of isoleucine (Ile) and α-methylaminoisobutyric acid (MeAIB) in both fibre types, DHT increased their uptake in the fast-twitch fibre bundles. This effect was reversed by inhibitors of protein translation, the epidermal growth factor receptor (EGFR), system A, system L, mTOR and MEK. However, it was relatively insensitive to inhibitors of transcription, androgen receptors and PI3K/Akt. Additionally, DHT treatment increased the expression of LAT2 and the phosphorylation of the EGFR in the fast-twitch fibre bundles and that of ERK1/2, RSK1/2 and ATF2 in both fibre types. Also, it decreased the phosphorylation of eEF2 and increased the incorporation of Ile into proteins in both fibre types. Most of these effects were reversed by EGFR and MEK inhibitors. From these findings we suggest that another physiological function of the acute/non-genomic actions of DHT in isolated mammalian skeletal muscle fibres is to stimulate amino acid uptake. This effect is mediated through the EGFR and involves the activation of the MAPK pathway and an increase in LAT2 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2 / metabolism
  • Amino Acid Transport System A / metabolism
  • Amino Acid Transport System y+ / biosynthesis*
  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport Systems / drug effects*
  • Amino Acids / metabolism*
  • Aminoisobutyric Acids / metabolism
  • Animals
  • Dihydrotestosterone / pharmacology*
  • Elongation Factor 2 Kinase / metabolism
  • ErbB Receptors / metabolism
  • Female
  • Fusion Regulatory Protein 1, Light Chains / biosynthesis*
  • Fusion Regulatory Protein 1, Light Chains / genetics
  • Isoleucine / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Biosynthesis / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Androgen / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Testosterone / metabolism
  • Testosterone / pharmacology

Substances

  • Activating Transcription Factor 2
  • Amino Acid Transport System A
  • Amino Acid Transport System y+
  • Amino Acid Transport Systems
  • Amino Acids
  • Aminoisobutyric Acids
  • Atf2 protein, mouse
  • Fusion Regulatory Protein 1, Light Chains
  • Receptors, Androgen
  • SLC7A8 protein, mouse
  • Slc38a2 protein, mouse
  • Isoleucine
  • Dihydrotestosterone
  • 2-(methylamino)isobutyric acid
  • Testosterone
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3
  • Eef2k protein, mouse
  • Elongation Factor 2 Kinase
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinases