Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic() Model.

Abstract

Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although themouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in thegene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of 'structural weakness', intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from(EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness indiaphragm was similar tomice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced indiaphragm (15% in EDL). Myofibrillar architecture was severely compromised insingle fibers of both muscle types, but more pronounced in diaphragm. Our results show that thegenotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background.