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 LeeJustin KolbDarren T HweeFady I MalikHenk L GranzierPublished in: International journal of molecular sciences (2019)
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.
Keyphrases
- skeletal muscle
- mechanical ventilation
- respiratory failure
- mouse model
- acute respiratory distress syndrome
- insulin resistance
- intensive care unit
- single molecule
- late onset
- photodynamic therapy
- resistance training
- extracorporeal membrane oxygenation
- heart rate
- traumatic brain injury
- oxidative stress
- immune response
- nuclear factor
- type diabetes
- adipose tissue
- smooth muscle
- myasthenia gravis
- blood flow