title: Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.
abstract: 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.
authors.affiliation: Preclinical Research and Development, San Francisco, California, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Russell
authors.forename: James J
authors.initials: JJ
authors.lastname: Hartman
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Hinken
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Muci
authors.forename: Raja
authors.initials: R
authors.lastname: Kawas
authors.forename: Lena
authors.initials: L
authors.lastname: Driscoll
authors.forename: Guillermo
authors.initials: G
authors.lastname: Godinez
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Marquez
authors.forename: William F
authors.initials: WF
authors.lastname: Browne
authors.forename: Michael M
authors.initials: MM
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Clarke
authors.forename: Scott E
authors.initials: SE
authors.lastname: Collibee
authors.forename: Marc
authors.initials: M
authors.lastname: Garard
authors.forename: Richard
authors.initials: R
authors.lastname: Hansen
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Jia
authors.forename: Pu-Ping
authors.initials: PP
authors.lastname: Lu
authors.forename: Hector
authors.initials: H
authors.lastname: Rodriguez
authors.forename: Khalil G
authors.initials: KG
authors.lastname: Saikali
authors.forename: Julia
authors.initials: J
authors.lastname: Schaletzky
authors.forename: Vipin
authors.initials: V
authors.lastname: Vijayakumar
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Albertus
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Claflin
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000302:isolation & purification / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000737:chemistry / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D014336:Troponin / Q000378:metabolism / Q000502:physiology; D019209:Troponin C / Q000819:agonists* / Q000378:metabolism*
chemical_list: C572767:CK-2017357; D007093:Imidazoles; D011719:Pyrazines; D014336:Troponin; D019209:Troponin C; D000251:Adenosine Triphosphatases; D009218:Myosins; D002118:Calcium