Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases

Nat Med. 2012 Feb 19;18(3):452-5. doi: 10.1038/nm.2618.


Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Calcium / metabolism*
  • Cattle
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / therapeutic use
  • Molecular Targeted Therapy
  • Muscle Contraction / drug effects
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Myasthenia Gravis / drug therapy
  • Myasthenia Gravis / metabolism
  • Myasthenia Gravis / pathology
  • Myosins / isolation & purification
  • Myosins / metabolism
  • Neuromuscular Diseases / drug therapy
  • Neuromuscular Diseases / metabolism*
  • Neuromuscular Diseases / pathology
  • Pyrazines / chemistry
  • Pyrazines / therapeutic use
  • Rabbits
  • Rats
  • Troponin / metabolism
  • Troponin / physiology
  • Troponin C / agonists*
  • Troponin C / metabolism*


  • CK-2017357
  • Imidazoles
  • Pyrazines
  • Troponin
  • Troponin C
  • Adenosine Triphosphatases
  • Myosins
  • Calcium