The anabolic/androgenic steroid nandrolone exacerbates gene expression modifications induced by mutant SOD1 in muscles of mice models of amyotrophic lateral sclerosis

Pharmacol Res. 2012 Feb;65(2):221-30. doi: 10.1016/j.phrs.2011.12.001. Epub 2011 Dec 10.

Abstract

Anabolic/androgenic steroids (AAS) are drugs that enhance muscle mass, and are often illegally utilized in athletes to improve their performances. Recent data suggest that the increased risk for amyotrophic lateral sclerosis (ALS) in male soccer and football players could be linked to AAS abuse. ALS is a motor neuron disease mainly occurring in sporadic (sALS) forms, but some familial forms (fALS) exist and have been linked to mutations in different genes. Some of these, in their wild type (wt) form, have been proposed as risk factors for sALS, i.e. superoxide dismutase 1 (SOD1) gene, whose mutations are causative of about 20% of fALS. Notably, SOD1 toxicity might occur both in motor neurons and in muscle cells. Using gastrocnemius muscles of mice overexpressing human mutant SOD1 (mutSOD1) at different disease stages, we found that the expression of a selected set of genes associated to muscle atrophy, MyoD, myogenin, atrogin-1, and transforming growth factor (TGF)β1, is up-regulated already at the presymptomatic stage. Atrogin-1 gene expression was increased also in mice overexpressing human wtSOD1. Similar alterations were found in axotomized mouse muscles and in cultured ALS myoblast models. In these ALS models, we then evaluated the pharmacological effects of the synthetic AAS nandrolone on the expression of the genes modified in ALS muscle. Nandrolone administration had no effects on MyoD, myogenin, and atrogin-1 expression, but it significantly increased TGFβ1 expression at disease onset. Altogether, these data suggest that, in fALS, muscle gene expression is altered at early stages, and AAS may exacerbate some of the alterations induced by SOD1 possibly acting as a contributing factor also in sALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Anabolic Agents / pharmacology
  • Androgens / pharmacology
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism
  • Mutation*
  • MyoD Protein / biosynthesis
  • MyoD Protein / genetics
  • MyoD Protein / metabolism
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Myogenin / biosynthesis
  • Myogenin / genetics
  • Myogenin / metabolism
  • Nandrolone / pharmacology*
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / drug effects

Substances

  • Anabolic Agents
  • Androgens
  • Muscle Proteins
  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Myog protein, mouse
  • Myogenin
  • SOD1 protein, human
  • Transforming Growth Factor beta
  • Nandrolone
  • Sod1 protein, mouse
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases