title: Muscle weakness in respiratory and peripheral skeletal muscles in a mouse model for nebulin-based nemaline myopathy.
abstract: Nemaline myopathy is among the most common non-dystrophic congenital myopathies, and is characterized by the presence of nemaline rods in skeletal muscles fibers, general muscle weakness, and hypotonia. Although respiratory failure is the main cause of death in nemaline myopathy, only little is known regarding the contractile strength of the diaphragm, the main muscle of inspiration. To investigate diaphragm contractility, in the present study we took advantage of a mouse model for nebulin-based nemaline myopathy that we recently developed. In this mouse model, exon 55 of Neb is deleted (NebΔExon55), a mutation frequently found in patients. Diaphragm contractility was determined in permeabilized muscle fibers and was compared to the contractility of permeabilized fibers from three peripheral skeletal muscles: soleus, extensor digitorum longus, and gastrocnemius. The force generating capacity of diaphragm muscle fibers of NebΔExon55mice was reduced to 25% of wildtype levels, indicating severe contractile weakness. The contractile weakness of diaphragm fibers was more pronounced than that observed in soleus muscle, but not more pronounced than that observed in extensor digitorum longus and gastrocnemius muscles. The reduced muscle contractility was at least partly caused by changes in cross-bridge cycling kinetics which reduced the number of bound cross-bridges. The severe diaphragm weakness likely contributes to the development of respiratory failure in NebΔExon55mice and might explain their early, postnatal death.
authors.affiliation: Department of Physiology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joureau
authors.affiliation: Department of Physiology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Josine M
authors.initials: JM
authors.lastname: de Winter
authors.affiliation: Department of Physiology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Kelly
authors.initials: K
authors.lastname: Stam
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.affiliation: Department of Physiology, VU University Medical Center Amsterdam, The Netherlands; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA. Electronic address: c.ottenheijm@vumc.nl.
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D018485:Muscle Fibers, Skeletal; D009124:Muscle Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D017696:Myopathies, Nemaline / Q000235:genetics / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000503:physiopathology*
chemical_list: D009124:Muscle Proteins; C035620:nebulin
keywords: Diaphragm; Nebulin; Nemaline myopathy; Respiratory failure