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.

Fig. 1. Overview of the Dystrophin Glycoprotein Complex with a Focus on Dystrophin.

a Schematic of both full-length dystrophin (Dp427m) and the small, truncated isoform, Dp71. Dystrophin has 24 spectrin repeats separated by four hinges, as well as having an actin-binding domain (ABD), cysteine-rich (CR) domain, and c-terminus (CT). Key binding partners are highlighted, including microtubules (MT) and the sarcolemma. There are many isoforms of Dp71, with Dp71m referring to muscle whilst Dp71b refers to neuronal tissue isoforms. Specifically, Dp71f refers to the neuronal cytoplasmic isoform. b The dystrophin-glycoprotein complex (DGC) as a whole situated at the sarcolemmal. Biomechanical forces are transduced between the ECM to F-actin. Note the potential cross-talk between the DGC and integrin adhesions, with Dp71 potentially having a role at focal adhesions. Created with Biorender.com.

Fig. 2. The dystrophin-glycoprotein complex has a central role in biomechanics.

a Dystrophin is central to mechanotransduction in healthy cardiac tissue. Biomechanical force is propagated along pre-tensed actin and microtubule (MT) cables which can then be transmitted to the nucleus. Moreover, this mechanism allows the cardiomyocyte to maintain tensegrity and respond to changes in the ECM and is perhaps involve in rigidity sensing. Stretch activated ion channels are regulated by dystrophin mediating appropriate Ca²⁺ ion entry, important for excitation-contraction coupling as well as signalling. Plectin associates with β-DG and is regulates ERK1/2 activity. b In DMD cardiac tissue, the absence of dystrophin leads to contraction-induced microtears of the sarcolemma, allowing excess entry of Ca²⁺ ions, leading to mitochondrial dysfunction and cell death. Moreover, the biomechanical signals are no longer propagated along actin and MT cables causing aberrant mechanotransduction. In the absence of dystrophin, the whole DGC can become absent or is heavily downregulated causing further disruption to downstream signalling. Created with Biorender.com.