A new look at cytoskeletal NOS‐1 and β‐dystroglycan changes in developing muscle and brain in control and mdx dystrophic mice

Abstract

Background: Loss of dystrophin profoundly affects muscle function and cognition. Changes in the dystrophin-glycoprotein complex (DGC) including disruption of nitric oxide synthase (NOS-1) may result from loss of dystrophin or secondarily after muscle damage. Disruptions in NOS-1 and beta-dystroglycan (bDG) were examined in developing diaphragm, quadriceps, and two brain regions between control and mdx mice at embryonic day E18 and postnatal days P1, P10, and P28. Age-dependent differential muscle loading allowed us to test the hypothesis that DGC changes are dependent on muscle use. Results: Muscle development, including loss of central nucleation and the localization of NOS-1 and bDG, was earlier in diaphragm than quadriceps; these features were differentially disrupted in dystrophic muscles. The NOS-1/bDG ratio, an index of DGC stability, was higher in dystrophic diaphragm (P10-P28) and quadriceps (P28) than controls. There were also distinct regional differences in NOS-1 and bDG in brain tissues with age and strain. NOS-1 increased with age in control forebrain and cerebellum, and in mdx cerebellum; NOS-1 and bDG were higher in control than mdx mouse forebrain. Conclusions: Important developmental changes in structure and muscle DGC preceded the hallmarks of dystrophy, and are consistent with the impact of muscle-specific differential loading during maturation. Age-dependent differences of immune-reactive NOS-1 and beta-dystroglycan in muscle are synchronized with stabilization of fiber membranes in development and similar to those in regenerative remodeling of muscle. Age-dependent maturation of immune-reactive NOS-1 and beta-dystroglycan (localization and amount) and the NOS-1/bDG ratio in the brain, vary between forebrain and cerebellum brain. The combined impact of dystrophin-deficiency and changes in NOS-1 and beta-dystroglycan localization and amount in diaphragm versus quadriceps muscles suggest differential loading (higher and earlier for diaphragm) contributes to the muscle-specific variability in onset and severity of the dystrophic phenotype.

Co‐administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy

“…Concomitantly, combined therapy showed more marked effects on the levels of b‐DG, leading to almost normal levels of this protein in the DIA in comparison to DFZ alone. b‐DG, which is reduced in the dystrophic fibres, is a main component of the dystrophin‐protein complex that links the cytoskeleton to the extracellular matrix, protects muscle fibres from mechanical stress and confers sarcolemmal reliance during contraction . Therefore, it is possible to suggest that the combined therapy improved sarcolemma stability by significantly increasing the levels of b‐DG, in agreement to other reports .…”

“…b-DG, which is reduced in the dystrophic fibres, is a main component of the dystrophin-protein complex that links the cytoskeleton to the extracellular matrix, protects muscle fibres from mechanical stress 18,19 and confers sarcolemmal reliance during contraction. 20 Therefore, it is possible to suggest that the combined therapy improved sarcolemma stability by significantly increasing the levels of b-DG, in agreement to other reports. 21,22 The increase in b-DG observed here may be related to the actions of both therapies (primarily the combined) in decreasing the levels of MMP-9 because DFZ and DOX have anti-MMP-9 activity 4,23 and b-DG is a substrate of MMP-9.…”

Fibrosis, low vascularity, and fewer slow fibers after rotator‐cuff injury

“…Dystrophin is important in maintaining fiber membrane integrity . It is reported to have additional function as a “molecular clock,” because it decreases in muscle with increasing age .…”

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…During this process and the accompanying growth, skeletal muscle fibers increase significantly in breadth (the mean diameter of hind limb muscle fibers increases fivefold) and even more in length (the average muscle fiber length for an adult is 20-30 mm, which is 1,000-fold longer than a mononucleated cell) (44). DG and the DGC are critical during this dynamic phase of sarcolemmal expansion (45)(46)(47). Contraction-induced injury before the onset of necrosis has been investigated in muscles of mouse pups deficient for both dystrophin and utrophin (48).…”