The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

Abstract

Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the extracellular matrix (ECM). Severing the link between the ECM and the intracellular cytoskeleton has a devastating impact on the homeostasis of skeletal muscle cells, leading to a range of muscular dystrophies. In addition, the loss of a functional DGC leads to progressive dilated cardiomyopathy and premature death. Dystrophin functions as a molecular spring and the DGC plays a critical role in maintaining the integrity of the sarcolemma. Additionally, evidence is accumulating, linking the DGC to mechanosignalling, albeit this role is still less understood. This review article aims at providing an up-to-date perspective on the DGC and its role in mechanotransduction. We first discuss the intricate relationship between muscle cell mechanics and function, before examining the recent research for a role of the dystrophin glycoprotein complex in mechanotransduction and maintaining the biomechanical integrity of muscle cells. Finally, we review the current literature to map out how DGC signalling intersects with mechanical signalling pathways to highlight potential future points of intervention, especially with a focus on cardiomyopathies.

Duchenne muscular dystrophy treatment with lentiviral vector containing mini-dystrophin gene in vivo

“…32 As can be seen, Spc-6R sequence contained the R1-R3 sequences which were directed bind with the sarcolemma. 35 From this, the translation product of Spc-6R might exhibit better sarcolemma localization property which could convert into better therapeutic effect. Spc-9R sequence contained R11-R15 domains which directly interacted with F-actin and sarcolemma.…”

“…Spc-9R sequence contained R11-R15 domains which directly interacted with F-actin and sarcolemma. 35 Spc-11R sequence contains both the R1-R3 and R11-R15 domains, which might perform better at preventing mechanical forces damage. Codon optimization was applied in all of the nucleotide sequences for higher expression level in mammal.…”

Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders

“…[63][64][65][66] Many other proteins are involved in force transmission and mechanosensing, such as dystrophin that acts as a spring linking the actin cytoskeleton of the myofibre to the ECM. 67 Further discussion of such complex mechanobiology for both individual myofibres and whole muscle lies beyond the scope of this review.…”

“…These interactions ultimately result, via mechanotransduction pathways, in biochemical signals that have wide‐ranging impacts on cell function and biology, ECM deposition and composition, and metabolism 63‐66 . Many other proteins are involved in force transmission and mechanosensing, such as dystrophin that acts as a spring linking the actin cytoskeleton of the myofibre to the ECM 67 . Further discussion of such complex mechanobiology for both individual myofibres and whole muscle lies beyond the scope of this review.…”

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

“…The Spc-9R sequence (Figure 1D) contained the R11-R15 domains, which directly interacted with F-actin and sarcolemma. 35 The Spc-11R sequence (Figure 1E) contains both the R1-R3 and R11-R15 domains, which might be better at preventing mechanical force damage. Codon optimization was performed in all of the nucleotide sequences for higher expression levels in mammals.…”