Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers

Neuromuscul Disord. 2014 Nov;24(11):960-72. doi: 10.1016/j.nmd.2014.06.001. Epub 2014 Jun 10.


Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93A) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789M/-) mutant mice), Schwartz-Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz-Jampel syndrome and nerve injury.

Keywords: Murine models; Neuromuscular diseases; Skeletal muscle weakness.

MeSH terms

  • Animals
  • Cholinesterases / genetics
  • Disease Models, Animal
  • Electromyography
  • Evoked Potentials, Motor / genetics
  • Evoked Potentials, Motor / physiology*
  • Gene Expression Regulation / genetics
  • Heparan Sulfate Proteoglycans / genetics
  • Mice
  • Mice, Transgenic
  • Motor Neurons / pathology*
  • Muscle Weakness / etiology*
  • Muscle, Skeletal / physiopathology
  • Muscular Diseases / complications*
  • Muscular Diseases / genetics
  • Mutation / genetics
  • Myofibrils / pathology*
  • Neuroeffector Junction / physiopathology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptors, Tumor Necrosis Factor / genetics
  • Superoxide Dismutase / genetics
  • TWEAK Receptor


  • Heparan Sulfate Proteoglycans
  • Receptors, Tumor Necrosis Factor
  • TWEAK Receptor
  • Tnfrsf12a protein, mouse
  • perlecan
  • SOD1 G93A protein
  • Superoxide Dismutase
  • MuSK protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Cholinesterases