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 transmission1. 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.
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Acknowledgements
The project described was supported by Cytokinetics, Inc. and by award number 1RC3NS070670-01 (F.I.M.) from the National Institute of Neurological Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the US National Institutes of Health.
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A.J.R., J.J.H., A.C.H., A.R.M., R.K., L.D., G.G., K.H.L., D.M., W.F.B., M.M.C., D.C., S.E.C., M.G., R.H., Z.J., P.-P.L., H.R., K.G.S., J.S., V.V., D.J.M., B.P.M. and F.I.M. are past or present employees of Cytokinetics, Inc. and own stock or stock options in Cytokinetics, Inc. D.L.A. and D.R.C. received research support from Cytokinetics, Inc.
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Russell, A., Hartman, J., Hinken, A. et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 18, 452–455 (2012). https://doi.org/10.1038/nm.2618
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DOI: https://doi.org/10.1038/nm.2618
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