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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Diaphragm/*physiology ; Imidazoles/*metabolism ; Muscle Proteins/*metabolism ; Muscle, Skeletal/*metabolism ; Myopathies, Nemaline/*metabolism ; Pyrazines/*metabolism ; Troponin/*metabolism; Animals ; Copper Transporter 1/genetics ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Contraction ; Muscle Proteins/genetics

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.

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R01AR053897 United States AR NIAMS NIH HHS; NA A Foundation for Building Strength

Keywords: diaphragm muscle; fast skeletal muscle troponin activators; isometric force; muscle contraction; nebulin; nemaline myopathy; shortening velocity

0 (CK-2017357)
0 (Copper Transporter 1)
0 (Imidazoles)
0 (Muscle Proteins)
0 (Pyrazines)
0 (Slc31a1 protein, mouse)
0 (Troponin)
02X6KNJ5EE (nebulin)

Date Created: 20191030 Date Completed: 20200331 Latest Revision: 20240721

20250114

PMC6829460

10.3390/ijms20205008

31658633