The role of branched fibres in the pathogenesis of Duchenne muscular dystrophy

Abstract

Branched fibres are a well-documented phenomenon of regenerating skeletal muscle. They are found in the muscles of boys with Duchenne muscular dystrophy (DMD), a severe condition of progressive muscle wasting caused by an absence of the sarcolemmal protein dystrophin, and in the muscles of the mdx mouse, an animal model of DMD. However, only a handful of studies have investigated how the physiological properties of these morphologically deformed fibres differ from those of normal fibres. These studies have found an association between the extent of fibre branching in mdx muscles and the susceptibility of these muscles to damage from eccentric contractions. They have also found that branched mdx muscle fibres cannot sustain maximal contractions in buffered Ca 2+ solutions, that branch points are sites of increased mechanical stress and that myofibrillar stucture is greatly disturbed at branch points. These findings have important implications for understanding the function of dystrophin. It is commonly thought that the role of dystrophin is mechanical stabilization of the sarcolemma, as numerous studies have shown that eccentric contractions damage mdx muscle more than normal muscle. However, the finding that branched mdx fibres are mechanically weakened raises the question, is it the lack of dystrophin or is it the fibre branching that leads to the vulnerability of mdx muscle to contractile damage? The importance of this question to our understanding of the function of dystrophin warrants further research into the physiological properties of branched fibres and how they differ from morphologically normal fibres.

Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy

“…Increased branching of myofibers has been reported in DMD patients, in embryonic and adult mdx mice and in mice lacking the olfactory receptor MOR23 or the intermediate filament desmin [44][45][46][47] . In adult mdx mice, increased branching has been proposed to result from abnormal fiber morphogenesis caused by defective myoblast fusion arising during the regeneration process stimulated by fiber degeneration 36,45,47 . However, the increased branching of mdx fibers differentiated from ES cells in vitro was unexpected as such a phenotype has not been reported in primary mdx myoblast cultures or in human DMD myoblast cultures.…”

Changes in plasma membrane Ca-ATPase and stromal interacting molecule 1 expression levels for Ca2+ signaling in dystrophic mdx mouse muscle

“…This may be a key element of Ca 2ϩ signaling within the junctional membranes and may be a major part of STIM1 signaling in muscle development (30). In dystrophic muscle, these changed levels of Ca 2ϩ signaling proteins and therefore the reshaped signals may be a critical link in attempts at initiating fiber regeneration in dystrophic muscle (4,17). STIM1-POST also regulates other key proteins such as Na ϩ -K ϩ -ATPase and SERCA (18).…”

Making muscle: skeletal myogenesisin vivoandin vitro

“…Moreover, myofibers differentiated from Dag1 null mESCs exhibit defects in the assembly of postsynaptic elements including acetylcholine receptor (AchR) clusters (Jacobson et al, 2001). Dmd mdx mPSC lines were shown to exhibit defects in myogenic differentiation and increased apoptosis , while Chal et al (2015) reported a branching defect characterized by an increased number of split fibers, a phenotype also seen in Duchenne muscular dystrophy (DMD) patients and the mdx mouse (Chan and Head, 2011). Finally, myoblasts derived from DMD human iPSCs were shown to exhibit fusion defects that could be corrected by dual inhibition of TGFβ and BMP signalings (Choi et al, 2016).…”