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

Abstract

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contractioninduced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contractioninduced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions. muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan

Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

“…), and because targeted knock‐down of dystroglycan made (non‐dystrophic) muscle fibres prone to EC‐induced loss of strength (Rader et al . ). The average intensity of β‐dystroglycan immunofluorescence in the extrasynaptic sarcolemma of our mdx control muscles was 60 ± 12% of the wild‐type muscle level.…”

“…; Rader et al . ). In particular conditional knock‐down of dystroglycan expression increased the susceptibility of healthy muscles to EC‐induced loss of force (Rader et al .…”

“…In particular conditional knock‐down of dystroglycan expression increased the susceptibility of healthy muscles to EC‐induced loss of force (Rader et al . ). Injection of AAV‐MuSK‐GFP into muscles of mdx mice led to increased expression of both MuSK and β‐dystroglycan throughout the sarcolemma (Figs and ).…”

“…Finally we examined the sarcolemmal density of β-dystroglycan, because dystroglycan is one of the DAPs that is expressed at reduced levels in mdx muscle fibres (Ohlendieck & Campbell, 1991;Johnson et al 2013), and because targeted knock-down of dystroglycan made (non-dystrophic) muscle fibres prone to EC-induced loss of strength (Rader et al 2016). The average intensity of β-dystroglycan immunofluorescence in the extrasynaptic sarcolemma of our mdx control muscles was 60 ± 12% of the wild-type muscle level.…”

Alterations in the muscle force transfer apparatus in aged rats during unloading and reloading: impact of microRNA‐31

“…β-Dystroglycan, through its partner α-dystroglycan, connects dystrophin to the extracellular matrix. Further, β-dystroglycan has recently been observed to play a key role in stabilizing dystrophin and limiting the amount of contraction-induced muscle injury (Rader et al 2016). Desmuslin is an intermediate filament that links the dystrophin binding protein α-dystrobrevin to desmin.…”