Cargando…
Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv
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 in...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829460/ https://www.ncbi.nlm.nih.gov/pubmed/31658633 http://dx.doi.org/10.3390/ijms20205008 |
_version_ | 1783465561454280704 |
---|---|
author | Lee, Eun-Jeong Kolb, Justin Hwee, Darren T. Malik, Fady I. Granzier, Henk L. |
author_facet | Lee, Eun-Jeong Kolb, Justin Hwee, Darren T. Malik, Fady I. Granzier, Henk L. |
author_sort | Lee, Eun-Jeong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6829460 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68294602019-11-18 Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv Lee, Eun-Jeong Kolb, Justin Hwee, Darren T. Malik, Fady I. Granzier, Henk L. Int J Mol Sci Article 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. MDPI 2019-10-10 /pmc/articles/PMC6829460/ /pubmed/31658633 http://dx.doi.org/10.3390/ijms20205008 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Eun-Jeong Kolb, Justin Hwee, Darren T. Malik, Fady I. Granzier, Henk L. Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title | Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title_full | Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title_fullStr | Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title_full_unstemmed | Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title_short | Functional Characterization of the Intact Diaphragm in a Nebulin-Based Nemaline Myopathy (NM) Model-Effects of the Fast Skeletal Muscle Troponin Activator tirasemtiv |
title_sort | functional characterization of the intact diaphragm in a nebulin-based nemaline myopathy (nm) model-effects of the fast skeletal muscle troponin activator tirasemtiv |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829460/ https://www.ncbi.nlm.nih.gov/pubmed/31658633 http://dx.doi.org/10.3390/ijms20205008 |
work_keys_str_mv | AT leeeunjeong functionalcharacterizationoftheintactdiaphragminanebulinbasednemalinemyopathynmmodeleffectsofthefastskeletalmuscletroponinactivatortirasemtiv AT kolbjustin functionalcharacterizationoftheintactdiaphragminanebulinbasednemalinemyopathynmmodeleffectsofthefastskeletalmuscletroponinactivatortirasemtiv AT hweedarrent functionalcharacterizationoftheintactdiaphragminanebulinbasednemalinemyopathynmmodeleffectsofthefastskeletalmuscletroponinactivatortirasemtiv AT malikfadyi functionalcharacterizationoftheintactdiaphragminanebulinbasednemalinemyopathynmmodeleffectsofthefastskeletalmuscletroponinactivatortirasemtiv AT granzierhenkl functionalcharacterizationoftheintactdiaphragminanebulinbasednemalinemyopathynmmodeleffectsofthefastskeletalmuscletroponinactivatortirasemtiv |