Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis

Amyotroph Lateral Scler. 2012 Jun;13(4):378-92. doi: 10.3109/17482968.2012.660953. Epub 2012 May 16.


We undertook a longitudinal study of the histological and biochemical changes at the neuromuscular junction (NMJ) in muscles of SOD1-G93A mice. We also assessed these functions in mice treated with a known heat shock protein inducer, arimoclomol. Tissue samples of treated and untreated mSOD mice were analysed for AChE and ChAT enzyme activities as markers of neuromuscular function. Sections of hindlimb muscles (TA, EDL and soleus) were also stained for succinate dehydrogenase and silver cholinesterase activities as well as for immunohistochemistry. Hsp70 levels were also measured from muscle samples using ELISA. Results showed that denervation and nerve sprouting were present at symptom onset in fast muscles, although slow muscles remained fully innervated. Cholinergic enzyme activities were reduced prior to denervation and declined further with disease progression. Reduction of endplate size, a slow to fast shift in muscle phenotype was also observed. Treatment with arimoclomol delayed the appearance of these changes, increased innervation, cholinergic enzyme activities and endplate size and reversed muscle fibre transformation. These beneficial effects of arimoclomol in muscles were accompanied by an increase in Hsp70 expression. In conclusion, our results indicate that pharmacological targeting of muscles at early stages of disease may be a successful strategy to ameliorate disease progression in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / drug effects*
  • Acetylcholinesterase / metabolism
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Choline O-Acetyltransferase / drug effects*
  • Choline O-Acetyltransferase / metabolism
  • Disease Models, Animal
  • Disease Progression
  • GPI-Linked Proteins / drug effects
  • GPI-Linked Proteins / metabolism
  • HSP70 Heat-Shock Proteins / drug effects
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Response
  • Hydroxylamines / pharmacology*
  • Longitudinal Studies
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / metabolism
  • Muscle Fibers, Fast-Twitch / drug effects
  • Muscle Fibers, Fast-Twitch / metabolism
  • Muscle Fibers, Slow-Twitch / drug effects
  • Muscle Fibers, Slow-Twitch / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / innervation*
  • Muscle, Skeletal / metabolism
  • Neuromuscular Junction / drug effects*
  • Neuromuscular Junction / metabolism
  • Succinate Dehydrogenase / drug effects
  • Succinate Dehydrogenase / metabolism
  • Superoxide Dismutase / genetics


  • GPI-Linked Proteins
  • HSP70 Heat-Shock Proteins
  • Hydroxylamines
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Succinate Dehydrogenase
  • Choline O-Acetyltransferase
  • Acetylcholinesterase
  • Ache protein, mouse
  • arimoclomol