The dystrophin-glycoprotein complex in the prevention of muscle damage

Abstract

Muscular dystrophies are genetically diverse but share common phenotypic features of muscle weakness, degeneration, and progressive decline in muscle function. Previous work has focused on understanding how disruptions in the dystrophin-glycoprotein complex result in muscular dystrophy, supporting a hypothesis that the muscle sarcolemma is fragile and susceptible to contraction-induced injury in multiple forms of dystrophy. Although benign in healthy muscle, contractions in dystrophic muscle may contribute to a higher degree of muscle damage which eventually overwhelms muscle regeneration capacity. While increased susceptibility of muscle to mechanical injury is thought to be an important contributor to disease pathology, it is becoming clear that not all DGC-associated diseases share this supposed hallmark feature. This paper outlines experimental support for a function of the DGC in preventing muscle damage and examines the evidence that supports novel functions for this complex in muscle that when impaired, may contribute to the pathogenesis of muscular dystrophy.

Figure 1

Sources of calcium entry in dystrophic muscle. (1) Disruptions to the DGC can result in instability of the sarcolemma that permits calcium entry through membrane tears when the sarcolemma is stretched during lengthening muscle contractions. (2) Activity of calcium leak, stretch-activated, and various TRP channels has been shown to be increased in dystrophin-deficient muscle and their inhibition in vivo can improve dystrophic pathology. (3) The ryanodine receptor has recently been shown to be hypernitrosylated in mdx muscle which may result in an increased leak of calcium from the sarcoplasmic reticulum.

Figure 2

The dystrophin-glycoprotein complex may participate in laminin-dependent signaling in skeletal muscle. Interactions shown in blue indicate interactions that have been shown to be increased when laminin is bound to dystroglycan. Interactions in pink indicate those that have been shown to be increased following a muscle contraction protocol. Since the phosphorylation of β-dystroglycan can bind a number of other SH2-domain containing proteins and can also interact with Grb2, it may participate in additional signal transduction cascades that have not yet been identified. It is important to remember that in many cases, these interactions have been studied in cell culture systems and the relevance of these interactions in muscle in vivo has not been extensively studied.

Figure 3

The dystrophin-glycoprotein complex transmits forces laterally at costameres in muscle. Longitudinal forces generated in sarcomeres are transmitted down myofibrils in muscle and forces are also transmitted laterally to the ECM and neighboring muscle fibers at costameres, at least in part through the dystrophin-glycoprotein complex (DGC). Recent data showing a loss of lateral force transmission in dystrophin-deficient muscle explains how the reduction or improper assembly of the DGC at the lateral membrane may contribute to overall muscle weakness and fragility.