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Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv

1
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA
2
Research and Early Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA
3
Medical Research Building, RM 325, 1656 E Mabel St, Tucson, AZ 85721, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 5008; https://doi.org/10.3390/ijms20205008
Received: 5 September 2019 / Revised: 5 October 2019 / Accepted: 6 October 2019 / Published: 10 October 2019
(This article belongs to the Special Issue Sarcomeric Proteins in Health and Disease)
Respiratory failure due to diaphragm dysfunction is considered a main cause of death in nemaline myopathy (NM) and we studied both isometric force and isotonic shortening of diaphragm muscle in a mouse model of nebulin-based NM (Neb cKO). A large contractile deficit was found in nebulin-deficient intact muscle that is frequency dependent, with the largest deficits at low–intermediate stimulation frequencies (e.g., a deficit of 72% at a stimulation frequency of 20 Hz). The effect of the fast skeletal muscle troponin activator (FSTA) tirasemtiv on force was examined. Tirasemtiv had a negligible effect at maximal stimulation frequencies, but greatly reduced the force deficit of the diaphragm at sub-maximal stimulation levels with an effect that was largest in Neb cKO diaphragm. As a result, the force deficit of Neb cKO diaphragm fell (from 72% to 29% at 20 Hz). Similar effects were found in in vivo experiments on the nerve-stimulated gastrocnemius muscle complex. Load-clamp experiments on diaphragm muscle showed that tirasemtiv increased the shortening velocity, and reduced the deficit in mechanical power by 33%. Thus, tirasemtiv significantly improves muscle function in a mouse model of nebulin-based nemaline myopathy. View Full-Text
Keywords: muscle contraction; isometric force; shortening velocity; fast skeletal muscle troponin activators; diaphragm muscle; nebulin; nemaline myopathy muscle contraction; isometric force; shortening velocity; fast skeletal muscle troponin activators; diaphragm muscle; nebulin; nemaline myopathy
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Lee, E.-J.; Kolb, J.; Hwee, D.T.; Malik, F.I.; Granzier, H.L. Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv. Int. J. Mol. Sci. 2019, 20, 5008.

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