Functional characterization of the intact diaphragm in a Nebulin-based nemaline myopathy (NM) model-effects of the fast skeletal muscle troponin activator tirasemtiv

Eun Jeong Lee, Justin Kolb, Darren T. Hwee, Fady I. Malik, Henk L. Granzier

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number5008
JournalInternational journal of molecular sciences
Volume20
Issue number20
DOIs
StatePublished - Oct 2 2019

Keywords

  • Diaphragm muscle
  • Fast skeletal muscle troponin activators
  • Isometric force
  • Muscle contraction
  • Nebulin
  • Nemaline myopathy
  • Shortening velocity

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint Dive into the research topics of 'Functional characterization of the intact diaphragm in a Nebulin-based nemaline myopathy (NM) model-effects of the fast skeletal muscle troponin activator tirasemtiv'. Together they form a unique fingerprint.

  • Cite this