From the Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706
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.
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,
INTRODUCTION
TOP
INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES
Costamere Structure and Function
TOP
INTRODUCTION
Costamere Structure and...
Costameres in Diseases of...
The Growing Costameric Protein...
Dynamic Aspects of Costameres
REFERENCES
-actinin, and
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).
View larger version (70K):
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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 -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.
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Costameres in Diseases of Muscle |
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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 -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.
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The Growing Costameric Protein Network |
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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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As an immediate test of these ideas, it is worth re-examining the
single instance where ablation of a dystrophin complex constituent (-dystrobrevin) results in muscular dystrophy with minimal apparent sarcolemmal damage (18). When compared with dystrophin-deficient mdx mice, the results with
-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
-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
-dystrobrevin
/
muscle. Furthermore,
several two-hybrid screens seeking to reveal candidate signaling
molecules regulated by
-dystrobrevin have instead identified several
novel intermediate filament proteins as
-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
-dystrobrevin may participate in lateral force transmission through
the costamere by coupling the intermediate filament cytoskeleton with
the dystrophin complex. If dystrophin,
-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
-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
-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.
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Dynamic Aspects of Costameres |
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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
-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
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 -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
-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.
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FOOTNOTES |
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* 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.
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
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ABBREVIATIONS |
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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.
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