Reduced Fatigue in Diaphragm Muscle of Merosin-Deficient dy/dy Dystrophic Mice

Abstract

Background: The muscular dystrophies comprise a heterogeneous group of disorders characterized by the absence of specific glycoproteins located at or near the cell membrane. The effects of dystrophin deficiency on diaphragm contractile function are well delineated, whereas the consequences of merosin (laminin α2) deficiency are not well defined. Objectives: Studies tested the hypothesis that genetic deficiency of merosin alters diaphragm fatigue resistance. Methods: Diaphragm contractile performance was tested in vitro using dy/dy dystrophic mice, which have the same biochemical defect as human classic congenital muscular dystrophies. Results: Twitch force/area was reduced by 46% in dy/dy dystrophic diaphragm, but isometric twitch kinetics were not altered. During repetitive 25-Hz stimulation, normal muscle demonstrated early force potentiation lasting 20 s. This was followed by a fast decline in force, with total force loss of ∼45% over 2 min. Force of dystrophic diaphragm also increased at the onset of stimulation, but remained elevated over baseline values for up to 70 s. Force decline thereafter was slow, amounting to ∼5% after 2 min and (in a subset of muscle samples stimulated for longer durations) ∼20% after 5 min. Relaxation rate of normal muscle slowed considerably during repetitive stimulation, whereas that of dy/dy dystrophic diaphragm remained constant. Conclusions: Merosin deficiency increases diaphragm force potentiation and reduces fatigue despite considerable muscle weakness. We speculate that the former may be important for maintaining ventilatory homeostasis in the merosin-deficient muscular dystrophies.