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

International Journal of Molecular Sciences

Justin Kolb¹  Eun-Jeong Lee¹  HenkL. Granzier¹  FadyI. Malik²  DarrenT. Hwee² 

[1] Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA;Research and Early Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA;

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

DOI  :  10.3390/ijms20205008

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown