Hypercontractile Airway Smooth Muscle is a Potential Driver of Respiratory Pathophysiology in Congenital Muscular Dystrophy 1A

Merosin deficient congenital muscular dystrophy (MDC1A) is a fatal, autosomal recessive disease caused by laminin α2 chain deficiency, preventing formation of the extracellular matrix protein laminin 211. Afflicted children experience profound muscle weakness and degeneration and often die prematurely from failure to thrive or acute respiratory failure resulting from weak respiratory muscles and progressive scoliosis. While diseased skeletal muscle has been well characterized, airway smooth muscle (ASM) has not been investigated and respiratory failure has been attributed solely to diaphragmatic weakness. Therefore, as a first step we investigated the contractile properties of ASM isolated from DyW mice, an animal model of MDC1A. Primary bronchial rings from 7wk WT and DyW mice were harvested and cleaned. Rings were mounted on wire triangles in a bath with oxygenated Krebs solution and connected to a force transducer to measure contractile responses to depolarizing 51mM KCl Krebs solution and 10 ‐5 M carbachol to activate G‐protein coupled muscarinic receptors. Rings were quick frozen and saved for histological analysis. Transverse sections (7 µm thick) were stained with Gomori Trichrome to differentiate ASM. Bronchial ASM cross sectional area (CSA) was calculated using NIS Basic Research software. Contractile forces were normalized to ASM CSA to determine ASM stress. The stress responses of DyW bronchi are significantly higher than WT in response to both 51 mM KCl (n WT =7, n DyW =3, p<0.002) and 10 ‐5 M carbachol (n WT =8, n DyW =4, p<0.006). These data indicate that ASM isolated from DyW mice are significantly hypercontractile compared to their WT counterpart, and could potentially contribute to respiratory insufficiency in MDC1A.