Introduction

Duchenne muscular dystrophy (DMD) is the most prevalent and severe form of human muscular dystrophy. While clinical descriptions of DMD date back to the 1850's, over 100 years passed before evidence suggested that the muscle cell plasma membrane, or sarcolemma, is compromised in DMD muscle. The molecular basis for DMD and its associated sarcolemmal instability became more clear with landmark studies published in the mid-to-late 1980's which identified the gene defective in DMD.¹ The DMD locus spans over 2.5 million bases distinguishing it as the largest gene in the human genome. The array of transcripts expressed from the DMD gene is complex due to the presence of multiple promoters and alternative splicing. The largest transcripts encode a four-domain protein with a predicted molecular weight of 427,000, named dystrophin. Dystrophin is the predominant DMD transcript expressed in striated muscle and DMD gene mutations, deletions or duplications most frequently result in a loss of dystrophin expression in muscle of patients afflicted with DMD. Based on its localization to the cytoplasmic face of the sarcolemma and sequence similarity with domains/motifs common to proteins of the actin-based cytoskeleton, dystrophin was hypothesized early on to play a structural role in anchoring the sarcolemma to the underlying cytoskeleton and protect the sarcolemma against stress imposed during muscle contraction or stretch. Biochemical studies aimed at confirming the hypothesized structure and function of dystrophin revealed its tight association with a multi-subunit complex, the so-named dystrophin-glycoprotein complex. Since its description, the dystrophin-glycoprotein complex has emerged as an important structural unit of muscle and also as a critical nexus for understanding muscular dystrophies arising from defects in several distinct genes.

Initial Isolation and Characterization of the Dystrophin-Glycoprotein Complex

Following close behind the identification of dystrophin as the protein missing from DMD muscle, the laboratory of Kevin Campbell demonstrated that dystrophin could be solubilized from the membrane vesicle fraction of skeletal muscle homogenates using the detergent digitonin and dramatically enriched by wheat germ agglutinin chromatography.² Given that the primary sequence contained no hydrophobic stretches to directly anchor dystrophin within the sarcolemma, it seemed most likely that dystrophin indirectly bound to wheat germ agglutinin through association with a membrane glycoprotein embedded in the sarcolemma and this idea was confirmed by experiments showing that dystrophin binding to wheat germ agglutinin was disrupted by chaotropic agents.² While anion-exchange chromatography further amplified and purified dystrophin over wheat germ agglutinin chromatography alone, numerous proteins remained in the peak dystrophin fractions and lectin blotting minimally revealed 12 copurifying glycoproteins as potential molecular partners for dystrophin.² Sucrose gradient centrifugation further resolved potential candidates to 9 proteins stained by Coomassie blue that were shown to strictly cosediment with dystrophin (Fig. 1): a singlet of 88,000, a triplet of 59,000, a singlet of 50,000, a doublet of 43,000, a singlet of 35,000 (but present at a molar ratio of ˜2:1 relative to dystrophin) and a singlet of 25,000 apparent M_r. Lectin blotting identified the 50,000, 43,000 and 35,000 species as glycoproteins and further revealed a broad band with an apparent molecular weight of 156,000.³ While the 156,000 M_r protein was poorly stained by Coomassie blue, its strong staining by wheat germ agglutinin and strict cosedimentation with dystrophin nonetheless elevated its candidacy as a sarcolemmal glycoprotein receptor for dystrophin.³ Thus, the list of potential dystrophin-associated proteins was narrowed down to 10 distinct M_r proteins, 5 of which were glycosylated.

Figure 1

Protein Constituents of the Dystrophin-Glycoprotein Complex. Shown on the left is a Coomassie blue-stained SDS-polyacrylamide gel loaded with dystrophin-glycoprotein complex purified from rabbit skeletal muscle. Molecular weight standards are indicated (more...)

Importantly, the Campbell lab was simultaneously pursuing a long-term project aimed at generating new monoclonal antibodies to calcium channels expressed in muscle. Since several calcium channel subunits were known to be glycosylated, wheat germ agglutinin-enriched fractions from detergent solubilized muscle membranes were used to immunize mice and screen hybridomas. Screening positive clones against dystrophin-enriched preparations yielded monoclonal antibodies to dystrophin, the 156,000 and 50,000 M_r dystrophin associated glycoproteins. ³ The new antibodies were instrumental in confirming through coimmunoprecipitation experiments the tight association of proteins that cosedimented with dystrophin as well as their colocalization with dystrophin at the sarcolemma.^3-5 Moreover, the monoclonal antibodies were critical in demonstrating that the abundance of the 156,000 and 50,000 M_r dystrophin-associated glycoproteins was dramatically reduced in DMD muscle.^3,6,7 Since these proteins colocalized with dystrophin in situ, copurified with dystrophin in stoichiometric amounts even after several distinct protein purification methodologies, and were diminished in dystrophin-deficient muscle, it was concluded that dystrophin was part of a large, hetero-oligomeric complex that may serve to stabilize the sarcolemma. Because several constituents were glycosylated and exploitation of this characteristic was so important in their isolation, the assembly of proteins associated with dystrophin was named the dystrophin-glycoprotein complex.

Additional biochemical analyses identified the 156,000 glycoprotein and 59,000 M_r triplet as peripheral membrane proteins⁵ while the 50,000, 43,000, 35,000 and 25,000 M_r species behaved as a subcomplex of integral membrane proteins.^5,8 Based on its extensive glycosylation^5,9 and peripheral membrane association, the 156,000 M_r dystrophin-associated glycoprotein was hypothesized to reside on the extracellular face of the sarcolemma and possibly function as a receptor for a component of the extracellular matrix. These hypotheses were born out with the cloning/sequencing of the gene encoding the 156,000 dystrophin-associated glycoprotein, which is expressed from a single transcript along with one of the 43,000 M_r dystrophin-associated glycoproteins.⁶ The propeptide is proteolytically processed into a wholly extracellular 156,000 subunit and a 43,000 M_r single-pass transmembrane subunit. Based on its extensive glycosylation and association with dystrophin, the 156,000 and 43,000 M_r subunits were renamed α- and β-dystroglycan, respectively. A screen of known extracellular matrix molecules for skeletal muscle α-dystroglycan binding activity identified laminin as the first extracellular ligand for α-dystroglycan.^6,9 Laminin-Sepharose pull-down of the entire dystrophin complex definitively demonstrated that α-dystroglycan was a stoichiometric component of the complex.⁹ These results also led to the hypothesis that the dystrophin-glycoprotein complex may play a role in muscle cell adhesion to the basal lamina.

Working independently, Ozawa and colleagues corroborated^10-12 many of the key findings first reported by the Campbell laboratory and they made some important original contributions in elucidating several of the protein-protein interactions within the complex (discussed below). However, Ozawa and colleagues strongly disputed two important conclusions of Campbell's group. First, they initially dismissed α-dystroglycan as an important component of the dystrophin-glycoprotein complex because it could not be stained by Coomassie blue.¹³ Ozawa and colleagues also strongly contested the initial identification of the 59,000 M_r α-dystrobrevin/syntrophin triplet as cytoplasmic peripheral membrane proteins because their experiments led them to conclude that one of the proteins was a transmembrane glycoprotein. ¹² In subsequent work,¹⁴ it is clear that Ozawa and colleagues ultimately concurred that α-dystroglycan is an important component of the complex and that syntrophins are nonglycosylated cytoplasmic proteins. Using limited proteolysis, wheat germ agglutinin chromatography and an array of site-specific antibodies, Ozawa and colleagues first demonstrated that the cysteine-rich and first half of the C-terminal domains of dystrophin were important for its binding to the glycoprotein complex.¹¹ By blot overlay assay, they showed that β-dystroglycan, and the 88,000 and 59,000 M_r dystrophin-associated proteins (α-dystrobrevins and syntrophins) directly bound the cysteine-rich and/or C-terminal domains of dystrophin,¹⁵ despite failing to reconcile their prior crosslinking studies where they concluded that the 50,000 and 35,000 M_r dystrophin-associated glycoproteins were directly associated with dystrophin and most important in anchoring it to the sarcolemma.¹⁰ Ozawa and colleagues also more conclusively showed¹⁶ that the dystrophin-glycoprotein complex could be dissociated into 3 sub-complexes consisting of α- and β-dystroglycan (dystroglycan complex), the 50,000, 43,000, and 35,000 M_r dystrophin-associated glycoproteins (sarcoglycan complex), dystrophin plus the 87,000 and 59,000 M_r dystrophin-associated proteins (dystrophin/dystrobrevin/syntrophin complex). However, it bears noting that several studies predating the work of Ozawa and colleagues reported data suggesting resolution of sub-complexes with similar molecular compositions. ^5,8,17,18

The largely biochemical studies described above suggested that the dystrophin-glycoprotein complex may function to physically couple the sarcolemmal cytoskeleton with the extracellular matrix (Fig. 2) and that loss of this structural linkage may render the sarcolemma more susceptible to damage when exposed to mechanical stress. The purified dystrophin-glycoprotein complex also provided a substrate for peptide sequencing and antibody production which yielded new probes important in the identification of genes encoding all dystrophin associated teins and elucidation of their respective roles in Duchenne and other forms of muscular dystrophy. Notably, the genes encoding several dystrophin-associated proteins cause forms of muscular dystrophy when mutated in humans or when knocked out in mice. Since dystrophin and its associated proteins are each a story in and of themselves, I will leave their detailed discussions to be elaborated in the specific chapters that follow. Below I will summarize the large body of evidence supporting an important mechanical role for the dystrophin-glycoprotein complex and then discuss its function within the larger protein network of skeletal muscle. Finally, I will propose an engineering design analogy that I believe best fits existing data.

Figure 2

Model of the Dystrophin-Glycoprotein Complex. Dystrophin is thought to physically couple the sarcolemma with the costameric cytoskeleton (see Fig. 3) through lateral association of its N-terminal and rod domains with cytoplasmic γ-actin filaments (more...)

In Support of a Mechanical Function for the Dystrophin-Glycoprotein Complex

Within skeletal myofibers, dystrophin is enriched in a discrete, rib-like lattice termed costameres.^19,20 Costameres are protein assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the sarcolemma in striated muscle cells (Fig. 3). A variety of data indicate that costameres are a striated muscle-specific elaboration of the focal adhesions expressed by nonmuscle cells.²¹ Classical experiments by Street²² and the Sangers²³ suggest that costameres function to laterally transmit contractile forces from sarcomeres across the sarcolemma to the extracellular matrix and ultimately to neighboring muscle cells. Lateral transmission of contractile force would be useful for maintaining uniform sarcomere length between adjacent actively contracting and resting muscle cells comprising different motor units within a skeletal muscle. It is also logical that the sites of lateral force transmission across the sarcolemma would be mechanically fortified to minimize stress imposed on the relatively labile lipid bilayer. Other results suggest that costameres may also coordinate an organized folding, or “festooning” of the sarcolemma,^22,24 which again may minimize stress experienced by the sarcolemmal bilayer during forceful muscle contraction or stretch. Thus, in support of its hypothesized mechanical function, dystrophin is enriched within a structure (the costamere) that likely transmits mechanical force to and through the sarcolemma.

Figure 3

The costameric cytoskeleton of striated muscle. Dystrophin is enriched at costameres, protein assemblies that circumferentially align in register with the Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the sarcolemma. (more...)

Consistent with its enrichment at costameres in normal muscle, the absence of dystrophin in humans and mice leads to a disorganized costameric lattice.^19,25-28 Extensive data consistently report that the dystrophin-deficient sarcolemma is exceedingly fragile^29-31 resulting in dramatically increased movement of membrane impermeant molecules across the sarcolemma of dystrophin-deficient muscle.^30-42 Both necrosis and sarcolemmal permeability of dystrophin-deficient muscle are exacerbated by physical exercise and improved by muscle immobilization. ^{33,35,39,42-45} Physiological studies have demonstrated that force production by dystrophin-deficient muscle is significantly decreased when normalized against muscle cross-sectional area.^40,41,46-59 Interestingly, force output by dystrophin-deficient muscle is hypersensitive to lengthening, or eccentric contraction^60,61 and the force decrement exhibited by dystrophin-deficient muscle undergoing eccentric contraction positively correlates with acutely increased sarcolemmal permeability.^{40,41,53-55,59-63} Immunofluorescence analysis of mechanically peeled sarcolemma has demonstrated that dystrophin at costameres is tightly attached to the sarcolemma²⁰ and its presence is necessary for strong coupling between the sarcolemma and costameric actin filaments comprised of cytoplasmic γ-actin.⁶⁴ Transgenic overexpression of the dystrophin homologue utrophin, or a dystrophin construct retaining the β-dystroglycan binding site and one actin binding domain is sufficient to restore coupling between the sarcolemma and costameric actin and rescue the sarcolemmal permeability defects accompanying dystrophin deficiency.^65,66 Dystrophin is also enriched in costameres of cardiac muscle.⁶⁷ Like skeletal muscle, dystrophin-deficient cardiac myocytes are abnormally vulnerable to mechanical stress-induced contractile failure and injury.^68,69 Finally, knockout of the dystroglycan or sarcoglycan complexes also causes muscular dystrophy that is accompanied by defects in sarcolemmal integrity.^70-79 When taken together, the above studies provide compelling evidence that the dystrophin-glycoprotein complex mainly functions to anchor the sarcolemma to costameres and stabilize it against the mechanical forces transduced through costameres during muscle contraction or stretch.

Expanding beyond the Dystrophin-Glycoprotein Complex

Since its initial description in 1990, many additional proteins have been shown to interact with different dystrophin-glycoprotein complex components (Fig. 4). Once the laminin α-chain G-domain was identified as the binding site for α-dystroglycan,⁸⁰ several other proteins containing homologous G-domain modules were interrogated and shown to bind α-dystroglycan with high affinity. The current list of such proteins includes agrins,^81-84 neurexins⁸⁵ and perlecan.^86,87 Like laminins, these proteins all bind to α-dystroglycan in a manner dependent on its oligosaccharide modifications.⁸⁸ In contrast, the chondroitin sulfate chains of the proteoglycan biglycan have been shown to mediate its binding to the core protein of α-dystroglycan.⁸⁹ While the functional significance of α-dystroglycan binding to several different extracellular matrix molecules is not fully clear, the results suggest that the dystroglycan complex may serve multiple roles that vary with the extracellular ligand to which it is bound. That agrins, neurexins and perlecan have all been implicated in various aspects of synapse formation or function.⁹⁰ further suggests participation by the dystroglycan complex in this process.

Figure 4

The Protein Interacting Network of the Dystrophin-Glycoprotein Complex. AQP4, aquaporin 4; Cav-3, caveolin-3; nNOS, neuronal nitric oxide synthase; SAPK3, stress-activated protein kinase 3 For a full list of supporting references, refer to the supplementary (more...)

Based on its sequence similarity with the calponin homology actin binding domains of β-spectrin and α-actinin, the N-terminal domain of dystrophin was hypothesized to bind actin filaments. Indeed, recombinant proteins encoding the dystrophin N-terminal domain do bind actin filaments,⁹¹ but with relatively low affinity.⁹² In contrast, purified dystrophin-glycoprotein complex bound actin filaments with substantially higher affinity compared to the isolated amino-terminal domain. The stoichiometry of binding however, suggested a more extensive lateral association between dystrophin and actin filaments than could be explained by actin binding solely through the N-terminal domain alone.⁹³ Mapping of the actin binding sites in dystrophin through F-actin cosedimentation of fragments after limited proteolysis led to the identification of a second actin binding site situated in the middle third of the dystrophin rod domain.⁹³ The spectrin-like repeats in this novel actin binding site were found to carry an excess of basic amino acid residues and were shown to bind acidic actin filaments largely through electrostatic interaction.⁹⁴ Because the middle rod actin binding site of dystrophin was separated from the amino-terminal actin binding domain by ˜1200 amino acids, the two sites were proposed to act in concert to effect an extended lateral association that could account for the measured stoichiometry of binding. In addition, the dystrophin-glycoprotein complex was shown to slow depolymerization of actin filaments in vitro.^93,95 These data supported a novel actin filament side-binding model for dystrophin and are entirely consistent with a role for the dystrophin-glycoprotein complex in mechanically coupling the sarcolemma with actin filaments of the costameric cytoskeleton.⁶⁴

The development of two-hybrid methodologies for the identification of protein-protein interactions has led to the discovery of several proteins that interact with the dystrophin-glycoprotein complex. Two-hybrid screens using α-dystrobrevin as bait identified several novel proteins.^96-98 Two of these proteins, synemin/desmuslin⁹⁸ and syncoilin,⁹⁹ are structurally related to intermediate filament proteins and interact with the classical intermediate filament protein desmin. Interestingly, mice knocked out for either α-dystrobrevin¹⁰⁰ or desmin^101,102 exhibit skeletal and cardiomyopathy, which suggests that mechanical coupling of the dystrophin-glycoprotein complex to the intermediate filament cytoskeleton is necessary for normal muscle function (see Chapter 5). Two hybrid screens using the cytoplasmic domains of sarcoglycans identified a skeletal muscle-specific form of filamin (γ-filamin) as a sarcoglycan interacting protein.103 Like dystrophin, filamin contains an N-terminal calponin homology actin binding domain and a large number of repeated motifs, although the repeats in filamin differ in structure from those in dystrophin. Interestingly, filamin A is recruited to focal adhesions of nonmuscle cells in response to local mechanical stress applied via collagen-coated magnetic beads.¹⁰⁴ Since γ-filamin is upregulated and recruited to the sarcolemma in dystrophin-deficient muscle,¹⁰³ it is tempt- ing to speculate that the dystrophin-deficient costamere may “sense” increased mechanical stress and attempt to compensate by recruitment of filamin. In addition to γ-filamin, several more actin binding proteins of costameres are upregulated in dystrophin-deficient muscle including the cytolinker plectin,¹⁰⁵ the integrin-associated proteins talin and vinculin¹⁰⁶ and the laminin receptor α7β1 integrin.^107,108 While not normally present at costameres, the dystrophin homologue utrophin is upregulated and recruited to costameres in dystrophin-deficient muscle.^64,65 Based on the protein interaction network illustrated in (Fig. 4), it seems most reasonable that all of these structural proteins are upregulated by the dystrophin-deficient muscle cell in an attempt to compensate for the absence of dystrophin by fortifying the weakened costamere through the recruitment of parallel mechanical linkages. Because dystrophy persists, these parallel linkages are either not completely redundant with the dystrophin-glycoprotein complex, or the compensatory upregulation/recruitment is incomplete. In support of the latter possibility, transgenic overexpression of utrophin^37,53,54 or α7 integrin¹⁰⁹ has been shown to further compensate for dystrophin deficiency. Thus, many of the proteins found to interact with the dystrophin-glycoprotein complex, or upregulated in its absence, appear to couple the complex with other structural elements of muscle, or form parallel mechanical links between the sarcolemma and myofibrillar apparatus. As such, these findings further reinforce an important mechanical function for the dystrophin-glycoprotein complex.

An Engineering Design Analogy

In many respects, the bulk of experimental data indicate that the dystrophin-glycoprotein complex functions in a manner analogous to the two-by-four (˜2 inch × 4 inch) timbers used to frame the typical American stick house. The architect utilizes two-by-fours as one structural element of a sturdy support matrix (ie., the costamere) intended to securely hold in place weatherproof siding and shingles (ie., the sarcolemma) as well as doors and windows (ie., ion channels and pumps) that allow for controlled movement of occupants, air and light both into and out of the house. When built to the architect's specifications, the house (or normal muscle cell) can withstand the stress imposed on it by extremes in weather such as high winds or heavy snowfall (or muscle contraction). If, however, the house is built during a shortage of two-by-fours (ie., the dystrophin-deficient muscle cell), the carpenter may be forced to substitute two-by-two timbers instead (ie., compensatory upregulation of partially redundant structural proteins). Such an alteration from original design may indeed allow the carpenter to construct a house that stands in calm weather. Conversely, the compromised structure may distort sufficiently under the force of gravity to cause doors and windows to stick or not close tightly. Moreover, the house built with substandard structural elements is certainly less likely to remain intact when more severe weather strikes.

Up to this point, the dystrophin-glycoprotein complex as two-by-four analogy has not taken into account that several interacting proteins suggest additional roles for the dystrophin-glycoprotein complex in organizing molecules involved in cellular signaling (Fig. 4). For example, α-syntrophin anchors neuronal nitric oxide synthase to the sarcolemma,¹¹⁰ which is necessary to properly regulate vascular perfusion in active muscle.^111,112 Other data indicate that MAP kinase signaling pathways are perturbed in dystrophin-deficient muscle.^113-115 Because the putative role(s) for the dystrophin-glycoprotein complex in cell signaling will no doubt be elaborated in subsequent chapters, the reader may be left wondering whether and how a role in signaling fits with its well-supported mechanical function. However, I believe the dystrophin-glycoprotein complex as two-by-four analogy fits well with its role in anchoring signaling molecules and also can explain the signaling perturbations observed in dystrophin-deficient muscle. While the architect clearly intended the two-by-fours as structural support for the weather-proofing and controlled entry components of the house, this primary function does not prevent the electrician, plumber, telephone and cable television installers from subsequently utilizing the two-by-four framework as a support to route and organize additional regulatory and communication systems (ie., cell signaling pathways) that further enhance functionality of the house. These additional systems would very reasonably be expected to malfunction in a house constructed of substandard structural components (ie., two-by-twos instead of two-by-fours) as a secondary consequence of its distortion under gravity or when challenged by more stringent weather conditions. Alternatively, one could as reasonably argue that mechanical distortion of the structurally weak two-by-two framework house may cause a short in the electrical system (ie., altered cell signaling) that in turn destroys the house by catastrophic fire (ie., apoptosis). In either case, I believe the architect could successfully argue that compromised mechanical integrity precipitated destruction of the house (and that was not his, but the carpenter's fault!). The mere association of signaling molecules with the dystrophin-glycoprotein complex and perturbations of signal transduction pathways in dystrophin-deficient muscle are not sufficient evidence to refute the compelling data supporting a primary mechanical function for the complex. Moreover, such data fail to provide compelling support that the dystrophin-glycoprotein complex actively regulates cellular signaling, or that altered signaling initiates the pathologies observed in dystrophin-deficient muscle. While these hypotheses certainly remain attractive (especially with respect to development of treatments for muscular dystrophy), the current challenge to the field is to design and perform experiments that rigorously test their validity.

In at least one respect, the dystrophin-glycoprotein complex as two-by-four analogy fails. When a house becomes too small for its occupants, the two-by-fours supporting static walls are demolished in order to expand rooms. In the case of muscle however, cells simultaneously grow under the influence of muscle contraction so the “two-by-four” framework of muscle cells must be sufficiently dynamic to expand with growth while simultaneously protecting against stress-induced membrane damage. Several studies have demonstrated that the dystrophin-glycoprotein complex and costameres are indeed dynamic structures capable of remodeling in vivo.²¹ However, a remaining challenge is to understand how such fascinating and opposing functions are effected at the molecular level, or perhaps at the level of interacting protein networks.

Acknowledgements

I thank Ariana Combs and Inna Rybakova for the blot images used in (Fig. 1) and Kevin Sonnemann for helpful discussions. The author is supported by grants from the Muscular Dystrophy Association and the National Institutes of Health (AR42423).

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