MINIREVIEW
Costameres: the Achilles' Heel of Herculean Muscle*,

James M. ErvastiDagger

From the Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706

    INTRODUCTION
TOP
INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

Like the ancient Greek hero Hercules, striated muscle is famous for performing impressive feats of strength. The procurement of food, breathing, and defense or escape from harm all depend on force production by skeletal muscle whereas contraction of cardiac muscle drives the circulatory system. As with the powerful Achilles, however, striated muscle possesses a small but mortal weakness. That weakness resides in the costamere, a relatively obscure element of the cortical cytoskeleton in striated muscle. The costamere has garnered new attention because several of its constituent proteins are defective in muscular dystrophies and cardiomyopathies. Furthermore, many costameric proteins physically interact with Z-disk or sarcolemmal proteins, which also cause myopathies when missing or defective. Finally, several newly identified costameric proteins suggest a role for the costamere/Z-disk axis in converting mechanical stimuli to alterations in cell signaling or gene expression. Here, I will summarize current understanding of costamere structure and function as well as its role in diseases of striated muscle.

    Costamere Structure and Function
TOP
INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

As originally described in the early 1980s (1, 2), costameres are subsarcolemmal 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. 1). In addition to costameres, the cortical cytoskeleton of striated muscle contains much finer hoop-like domains aligned in register with the M line and longitudinal strands that appear to connect M line components with costameres (3). Although several constituents of costameres have also been detected in the M line and longitudinal elements (3), these cytoskeletal elements are not observed consistently so information about their composition and putative function is minimal. Therefore, the use of the term costamere in this review refers only to peripheral Z-disk structures as defined originally (1, 2). A variety of data indicate that costameres are a striated muscle-specific elaboration of the focal adhesions expressed by non-muscle cells. The canonical focal adhesion protein vinculin is also a founding member of costameres (1), and its immunofluorescence staining pattern in striated muscle remains the standard by which many other costameric proteins have been identified. Other focal adhesion proteins found in costameres include talin, alpha -actinin, and beta 1 integrins (4). Although not restricted to costameres, immunoelectron micrograph studies indicated that the intermediate filament protein desmin constitutes one of the physical links between the Z-disk and sarcolemma (4).


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Fig. 1.   Cellular location of costameres in striated muscle. Shown in A is a schematic diagram illustrating costameres as circumferential elements that physically couple peripheral myofibrils to the sarcolemma in periodic register with the Z-disk. The protein composition of costameres is shown in expanded form in Fig. 2. Shown in B is an inside-out sarcolemma that was mechanically peeled from a single myofiber and stained with antibodies to gamma -actin to reveal the costameric cytoskeleton. Bar, 10 µm. B is reproduced from Ref. 17 by copyright permission of The Rockefeller University Press.

Classic experiments by Street (5), Craig and colleagues (1), and Sanger and colleagues (6) suggest that costameres may 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 have long suggested that costameres may coordinate an organized folding, or "festooning" of the sarcolemma (3, 5), which again may minimize the stress experienced by the sarcolemmal bilayer during forceful muscle contraction or stretch.

    Costameres in Diseases of Muscle
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INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

The importance of the costamere to normal muscle function has emerged from investigations into the causes of muscular dystrophies (7, 8) and dilated cardiomyopathies (9). Dystrophin, the product of the gene that is defective in Duchenne muscular dystrophy, was the first disease-relevant protein shown to be enriched at costameres (3). Through its cysteine-rich and C-terminal domains, skeletal muscle dystrophin interacts with a biochemically stable, hetero-oligomeric protein complex that includes the integral membrane dystroglycan and sarcoglycan-sarcospan subcomplexes and subsarcolemmal dystrobrevins and syntrophins (7, 8). The N-terminal and large middle rod domains of dystrophin act in concert to effect an extensive lateral association with actin filaments (10). Although dystrophin is not required for the assembly of costameres, its absence in humans and mice leads to a disorganized costameric lattice and disruption of sarcolemmal integrity (7, 8). Most notably, extensive data report dramatically increased movement of membrane-impermeant molecules both into and out of dystrophin-deficient muscle cells (11, 12) whereas functional studies have demonstrated that specific force production by muscle lacking dystrophin is decreased (13) and hypersensitive to lengthening or eccentric contraction (14, 15). Moreover, the force decrement exhibited by dystrophin-deficient muscle undergoing eccentric contraction positively correlates with acutely increased sarcolemmal permeability (14, 15). Immunofluorescence analysis of mechanically peeled sarcolemma showed that dystrophin is tightly attached to the sarcolemma (16) and that its presence is necessary for strong coupling between the sarcolemma and gamma -actin filaments of costameres (17). With one notable exception (18, see below), ablation of other components in the dystrophin complex that cause muscular dystrophy also cause defects in sarcolemmal integrity (19-21). Thus, there is good evidence that the dystrophin complex functions to anchor the sarcolemma to costameres and stabilize the sarcolemma against physical forces transduced through costameres during muscle contraction or stretch.

    The Growing Costameric Protein Network
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INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

An extensive list of costameric proteins and their putative molecular partners has been painstakingly documented by many laboratories over the past 20 years. Because elucidation of its molecular composition was drawn out over many years and performed by diverse groups, it may not be obvious just how complex the costameric protein assembly really is. In the spirit of proteomics, I have therefore attempted to illustrate the interacting protein network of costameres (Fig. 2), based mainly on results from immunofluorescence colocalization, co-immunoprecipitation, and in vitro binding assays. In addition, the identification of novel costameric proteins has also recently surged from the results of two-hybrid screens. Based on the extensive array of interconnected actin binding and intermediate filament proteins apparent in Fig. 2, it would seem difficult to argue against a role for costameres in physically coupling the force-generating sarcomeres to the sarcolemma and beyond. More striking are the large number of structural proteins within costameres or adjoining structures that cause muscle disease when mutated or ablated. Although the complexity of the network illustrated in Fig. 2 further suggests that costameric subcomplexes may perform specialized subfunctions, the subcomplexes likely don't function independently but rather must integrate their functions with the network at large. Finally, given each protein's interaction with a unique set of costameric proteins, it seems likely that the cellular phenotypes caused by independent ablation of two interacting proteins may differ because the loss of each perturbs a different suite of interacting proteins.


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Fig. 2.   Delineation of the costameric protein network (the hard way). Proteins illustrated were previously shown to co-localize with an established costameric protein and/or interact with a costameric protein. Numerous proteins co-distribute with the Z-disk throughout the core of the myofibrillar apparatus but also overlap and biochemically interact with costameric proteins at the myofiber periphery. Proteins connected by lines have been reported to interact based on co-immunoprecipitation, in vitro binding assays, or two-hybrid analysis. Genes that cause muscular dystrophy and/or cardiomyopathy when mutated in humans or knocked-out in mice encode proteins highlighted in red. Ablation of the proteins highlighted in green caused no discernible muscle phenotype. Proteins outlined in blue have been implicated in regulating cell signaling and/or gene expression. Proteins primarily associated with the extracellular matrix, sarcolemma, or Z-disk are grouped within shaded areas.

As an immediate test of these ideas, it is worth re-examining the single instance where ablation of a dystrophin complex constituent (alpha -dystrobrevin) results in muscular dystrophy with minimal apparent sarcolemmal damage (18). When compared with dystrophin-deficient mdx mice, the results with alpha -dystrobrevin-null mice certainly support the idea that the loss of two different interacting costameric proteins can result in unique phenotypic outcomes possibly due to disruption of distinct subsets of interacting proteins. In the absence of sarcolemmal damage, it was suggested that alpha -dystrobrevin (and the dystrophin complex) may play a non-mechanical and perhaps signaling role in striated muscle (18). However, no defect in muscle cell signaling has been identified that can account for the dystrophic phenotype observed in alpha -dystrobrevin -/- muscle. Furthermore, several two-hybrid screens seeking to reveal candidate signaling molecules regulated by alpha -dystrobrevin have instead identified several novel intermediate filament proteins as alpha -dystrobrevin interactors (22-24). Two of these proteins, synemin (24) and syncoilin (25), also interact with desmin. Striated muscle of mice lacking desmin exhibits numerous structural and functional abnormalities (26, 27). Most notably, desmin -/- muscle is weak (27-29) but shows no force drop after eccentric contraction (28, 29). Although explicit tests of increased sarcolemmal permeability have not been reported for desmin-null muscle, the absence of force drop with eccentric contraction (28, 29) suggests these mice may experience little membrane disruption compared with mdx mice exhibiting large force drops correlating strongly with increased sarcolemmal permeability (14, 15). Lateral force transmission is, however, greatly diminished in desmin-null muscle (30). Taken together, these results suggest that alpha -dystrobrevin may participate in lateral force transmission through the costamere by coupling the intermediate filament cytoskeleton with the dystrophin complex. If dystrophin, alpha -dystrobrevin, and desmin are all physically connected within the costamere, how then can we reconcile significant membrane damage observed in mdx muscle with the minimal membrane defect accompanying myopathies in alpha -dystrobrevin -/- and desmin -/- mice? In this instance, it is informative to consider individual protein function from the broader perspective of an integrated costameric protein network (Fig. 2). Ablation of each protein clearly perturbs the function of the network as evidenced by muscle phenotype. However, the observed cellular phenotypes may differ because the absence of each protein disrupts the subfunctions performed by different clusters of interacting proteins within the costamere. In the case of alpha -dystrobrevin and desmin, loss of either protein may uncouple lateral force transmission through costameres to primarily disrupt sarcomere function (i.e. decreased force production) while sparing membrane integrity. Like desmin -/- muscle, dystrophin-deficient muscle also exhibits diminished force production, suggesting a contribution to normal sarcomere function. However, sarcolemmal damage additionally manifests as a cellular defect in dystrophin-deficient muscle because dystrophin also functions to mechanically stabilize the sarcolemma against potentially damaging lateral forces, regardless of how force is transmitted through the costameric network.

The concept of dystrophin as a multidimensional mechanical element of costameres has recently received apparent challenge from results obtained with transgenic mdx mice overexpressing neuronal nitric-oxide synthase or truncated dystrophin constructs. In the former case, Tidball and colleagues (31) observed restoration of nitric oxide (NO)1 levels to normal and a dramatic reduction in several parameters of muscular dystrophy, including sarcolemmal damage. Additional experiments indicated that restoration of NO inhibited muscle inflammation, which the authors concluded is the overriding cause of membrane damage in mdx muscle. However, this study only measured passive uptake of a membrane-impermeant dye into resting muscles without assessing whether the greatly increased contraction-induced sarcolemmal permeability of mdx muscle (14, 15) was also corrected. In addition, the lower serum creatine kinase levels of 4-week-old mdx mice overexpressing neuronal nitric-oxide synthase were not significantly different from mdx mice at 3 months of age suggesting a delay in onset of sarcolemmal damage. Finally, this group (32) and others (33) had previously reported that elevated NO could induce up-regulation of the costameric proteins talin, vinculin, and the dystrophin homologue utrophin. Given that overexpression of utrophin has been shown to reverse the mechanical phenotypes of dystrophin-deficient muscle (34), including strong coupling between costameric actin and the sarcolemma (35), it seems likely that normalization of NO levels may have mechanically stabilized the sarcolemma of mdx muscle through increased expression of other structural proteins within costameres. From yet another perspective, Chamberlain and colleagues (36) recently assessed whether the retinal isoform of dystrophin, Dp260, could rescue mdx muscle. Dp260 lacks the N-terminal actin binding domain and spectrin repeats 1-10 but retains the basic middle rod actin binding site (37). Dp260/mdx muscle showed normal retention of costameric actin on mechanically peeled sarcolemma, normal resistance to contraction-induced injury, and reduced inflammation and fibrosis. However, Dp260/mdx muscle exhibited evidence of muscle cell necrosis/regeneration compared with wild type controls and diminished force production similar to that measured in mdx muscle. Thus, like desmin -/- muscle, Dp260/mdx muscle exhibited a mechanical defect (decreased force production) without evidence of sarcolemmal damage. These examples all underscore the idea that the absence of sarcolemmal damage does not preclude a mechanical defect residing elsewhere in the myofiber cytoskeleton as the cause of muscular dystrophy. The challenge remains to develop methods to identify and measure non-sarcolemmal mechanical defects associated with the loss of costameric proteins.

    Dynamic Aspects of Costameres
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INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

Just because costameres are essential mechanical elements of striated muscle does not mean that they are static or unchanging. For example, it was recently shown that the costameric component of gamma -filamin is up-regulated in dystrophin-deficient muscle (38). Another study demonstrated recruitment of filamin to focal adhesions experiencing local mechanical stress applied via collagen-coated magnetic beads (39). Taken together, these results suggest that the dystrophin-deficient costamere may "sense" increased mechanical stress and attempt to compensate through filamin recruitment. Three additional studies demonstrate more directly that mechanical tension is critical in regulating costameric protein expression, stability, and organization. In the first (32), it was shown that the costamere constituents talin and vinculin are up-regulated in response to muscle contraction through a mechanism involving neuronal nitric-oxide synthase (also a constituent of costameres). In the second study (40), isolated cardiac myocytes were mechanically unloaded by inhibition of contraction with a calcium channel antagonist. Within 24 h, costameric staining for vinculin and beta 1 integrin was abrogated, but could be recovered by washout of the inhibitor or by application of static stretch. In the third study (41), the normally transverse banding pattern of several costameric proteins (dystrophin, syntrophin, and dystroglycan) was shown to dramatically reorient longitudinally in skeletal muscle after 3 days of denervation. The costamere reorganization induced by denervation could be reversed by electrical stimulation or application of muscle agrin. Interestingly, extracellular laminin-2 remained in the normal costamere orientation in denervated muscle suggesting that coupling between cell surface receptors of costameres and the extracellular matrix is under neural control. Overall, the results of these studies indicate that costameres are highly dynamic structures responsive to (and dependent on) mechanical, electrical, and chemical stimuli.

Another spate of recent publications supports an exciting role for the costamere/Z-disk axis in mechanotransduction, the dynamic process through which mechanical stimuli are sensed by muscle cells and converted into biochemical responses (42). The protein Csl/Smpx localizes to costameres (Fig. 2) in adult skeletal muscle (43) and is dramatically up-regulated in response to passive stretch in vivo (44). Although its costameric binding partners are unknown and Csl/Smpx knock-out mice exhibit no obvious muscle phenotype, in vitro experiments suggest that Csl/Smpx can enhance insulin-like growth factor-1-mediated activation of nuclear factor of activated T cells (NFAT) and myocyte enhancer-binding factor (MEF2) transcription factor families (43). The NFAT and MEF2 families are famous for regulating gene expression associated with striated muscle hypertrophy and fiber type in response to several stimuli, including mechanical stress (45). Of related interest, NFATc was recently localized to the Z-disk in unstimulated skeletal muscle fibers but translocated to the nucleus upon specific patterns of electrical stimulation (46). Certainly, electrical stimuli act in part through local changes in calcium near the Z-disk (47). However, the stimulated muscles were also undergoing active contraction (47) so it is possible that the electrical stimulation protocol induced a specific mechanical stress that was communicated to NFATc by Csl/Smpx or through its physical association with calcineurin and calsarcins (Fig. 2) (48, 49). Still other results (50) suggest that nuclear translocation of NFATc may be perturbed in dystrophin-deficient muscle due to increased phosphorylation by the stress-activated protein kinase (SAPK) JNK1. The binding of SAPK3 to costameric alpha -syntrophin (51) further tempts speculation that the dystrophin glycoprotein complex may somehow participate in signaling through stress-activated pathways. Alternatively, filamin binds to the upstream activator kinase of JNK1 (MKK4), whereas JNK activation is absent in filamin-deficient cells (52). Thus, it is possible that recruitment of gamma -filamin to costameres in dystrophin-deficient muscle (38) leads to abnormal JNK1 activation and perturbation of transcriptional regulation by NFATc.

Finally, it remains to be determined how stimuli in the form of mechanical force may be converted into altered biochemical responses. Clearly, mechanosensitive ion channels provide one established mechanism at the interface between the cytoskeleton and membrane (42), but this alone seems unlikely to fully explain mechanotransduction at the costamere and Z-disk, particularly deep within a myofiber. Alternatively, it has been suggested that physical distortion may reveal (or obscure) new binding sites within a network of interacting proteins that could transiently bring together (or dissociate) signaling molecules with their effectors (53). In support of this possibility (at least in non-muscle cells), Sawada and Sheetz (54) recently demonstrated differences in the array of cytoplasmic proteins bound to Triton-extracted cytoskeletal "ghosts" adhered to flexible substratum that were stretched compared with unstretched specimens. This type of approach is certainly amenable to striated muscle, where it may confirm the costamere/Z-disk axis as a critical site of mechanotransduction and identify the important molecular players. Future studies are certain to reveal even more apollonian features integrated within the Achilles' heel of muscle.

    FOOTNOTES

* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. This is the second article of four in the "Skeletal Muscle Basement Membrane-Sarcolemma-Cytoskeleton Interaction Minireview Series."

The online version of this article (available at http://www.jbc.org) contains the complete bibliography supporting Fig. 2.

Dagger Supported by National Institutes of Health Grant AR42423 and grants from the Muscular Dystrophy Association. To whom correspondence should be addressed: Dept. of Physiology, 127 Service Memorial Institute, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-3419; Fax: 608-265-5512; E-mail: ervasti@physiology.wisc.edu.

Published, JBC Papers in Press, January 29, 2003, DOI 10.1074/jbc.R200021200

    ABBREVIATIONS

The abbreviations used are: NO, nitric oxide; NFAT, nuclear factor of activated T cells; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase.

    REFERENCES
TOP
INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES

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