Costameres: the Achilles' Heel of Herculean Muscle (2003)

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 (1Pardo J.V. D'Angelo Siliciano J. Craig S.W. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1008-1012Crossref PubMed Scopus (332) Google Scholar, 2Craig S.W. Pardo J.V. Cell Motil. 1983; 3: 449-462Crossref PubMed Scopus (169) Google Scholar), 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 (3Porter G.A. Dmytrenko G.M. Winkelmann J.C. Bloch R.J. J. Cell Biol. 1992; 117: 997-1005Crossref PubMed Scopus (192) Google Scholar). Although several constituents of costameres have also been detected in the M line and longitudinal elements (3Porter G.A. Dmytrenko G.M. Winkelmann J.C. Bloch R.J. J. Cell Biol. 1992; 117: 997-1005Crossref PubMed Scopus (192) Google Scholar), 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 (1Pardo J.V. D'Angelo Siliciano J. Craig S.W. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1008-1012Crossref PubMed Scopus (332) Google Scholar, 2Craig S.W. Pardo J.V. Cell Motil. 1983; 3: 449-462Crossref PubMed Scopus (169) Google Scholar). 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 (1Pardo J.V. D'Angelo Siliciano J. Craig S.W. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1008-1012Crossref PubMed Scopus (332) Google Scholar), 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, α-actinin, and β1 integrins (4Patel T.J. Lieber R.L. Exerc. Sport Sci. Rev. 1997; 25: 321-363Crossref PubMed Scopus (155) Google Scholar). 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 (4Patel T.J. Lieber R.L. Exerc. Sport Sci. Rev. 1997; 25: 321-363Crossref PubMed Scopus (155) Google Scholar). Classic experiments by Street (5Street S.F. J. Cell. Physiol. 1983; 114: 346-364Crossref PubMed Scopus (324) Google Scholar), Craig and colleagues (1Pardo J.V. D'Angelo Siliciano J. Craig S.W. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 1008-1012Crossref PubMed Scopus (332) Google Scholar), and Sanger and colleagues (6Danowski B.A. Imanaka-Yoshida K. Sanger J.M. Sanger J.W. J. Cell Biol. 1992; 118: 1411-1420Crossref PubMed Scopus (228) Google Scholar) 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 (3Porter G.A. Dmytrenko G.M. Winkelmann J.C. Bloch R.J. J. Cell Biol. 1992; 117: 997-1005Crossref PubMed Scopus (192) Google Scholar, 5Street S.F. J. Cell. Physiol. 1983; 114: 346-364Crossref PubMed Scopus (324) Google Scholar), which again may minimize the stress experienced by the sarcolemmal bilayer during forceful muscle contraction or stretch. The importance of the costamere to normal muscle function has emerged from investigations into the causes of muscular dystrophies (7Cohn R.D. Campbell K.P. Muscle Nerve. 2000; 23: 1456-1471Crossref PubMed Scopus (426) Google Scholar,8Blake D.J. Weir A. Newey S.E. Davies K.E. Physiol. Rev. 2002; 82: 291-329Crossref PubMed Scopus (925) Google Scholar) and dilated cardiomyopathies (9Chien K.R. Nature. 2001; 407: 227-232Crossref Scopus (167) Google Scholar). 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 (3Porter G.A. Dmytrenko G.M. Winkelmann J.C. Bloch R.J. J. Cell Biol. 1992; 117: 997-1005Crossref PubMed Scopus (192) Google Scholar). 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 (7Cohn R.D. Campbell K.P. Muscle Nerve. 2000; 23: 1456-1471Crossref PubMed Scopus (426) Google Scholar, 8Blake D.J. Weir A. Newey S.E. Davies K.E. Physiol. Rev. 2002; 82: 291-329Crossref PubMed Scopus (925) Google Scholar). The N-terminal and large middle rod domains of dystrophin act in concert to effect an extensive lateral association with actin filaments (10Rybakova I.N. Amann K.J. Ervasti J.M. J. Cell Biol. 1996; 135: 661-672Crossref PubMed Scopus (189) Google Scholar). 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 (7Cohn R.D. Campbell K.P. Muscle Nerve. 2000; 23: 1456-1471Crossref PubMed Scopus (426) Google Scholar, 8Blake D.J. Weir A. Newey S.E. Davies K.E. Physiol. Rev. 2002; 82: 291-329Crossref PubMed Scopus (925) Google Scholar). Most notably, extensive data report dramatically increased movement of membrane-impermeant molecules both into and out of dystrophin-deficient muscle cells (11Weller B. Karpati G. Carpenter S. J. Neurol. Sci. 1990; 100: 9-13Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 12Matsuda R. Nishikawa A. Tanaka H. J. Biochem. (Tokyo). 1995; 118: 959-964Crossref PubMed Scopus (279) Google Scholar) whereas functional studies have demonstrated that specific force production by muscle lacking dystrophin is decreased (13Lynch G.S. Hinkle R.T. Chamberlain J.S. Brooks S.V. Faulkner J.A. J. Physiol. (Lond.). 2001; 535: 591-600Crossref Scopus (250) Google Scholar) and hypersensitive to lengthening or eccentric contraction (14Petrof B.J. Shrager J.B. Stedman H.H. Kelly A.M. Sweeney H.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3710-3714Crossref PubMed Scopus (1184) Google Scholar, 15Moens P. Baatsen P.H. Marechal G. J. Muscle Res. Cell Motil. 1993; 14: 446-451Crossref PubMed Scopus (265) Google Scholar). Moreover, the force decrement exhibited by dystrophin-deficient muscle undergoing eccentric contraction positively correlates with acutely increased sarcolemmal permeability (14Petrof B.J. Shrager J.B. Stedman H.H. Kelly A.M. Sweeney H.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3710-3714Crossref PubMed Scopus (1184) Google Scholar, 15Moens P. Baatsen P.H. Marechal G. J. Muscle Res. Cell Motil. 1993; 14: 446-451Crossref PubMed Scopus (265) Google Scholar). Immunofluorescence analysis of mechanically peeled sarcolemma showed that dystrophin is tightly attached to the sarcolemma (16Straub V. Bittner R.E. Léger J.J. Voit T. J. Cell Biol. 1992; 119: 1183-1191Crossref PubMed Scopus (117) Google Scholar) and that its presence is necessary for strong coupling between the sarcolemma and γ-actin filaments of costameres (17Rybakova I.N. Patel J.R. Ervasti J.M. J. Cell Biol. 2000; 150: 1209-1214Crossref PubMed Scopus (307) Google Scholar). 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 (19Hack A.A. Ly C.T. Jiang F. Clendenin C.J. Sigrist K.S. Wollmann R.L. McNally E.M. J. Cell Biol. 1998; 142: 1279-1287Crossref PubMed Scopus (256) Google Scholar, 20Duclos F. Straub V. Moore S.A. Venzke D.P. Hrstka R.F. Crosbie R.H. Durbeej M. Lebakken C.S. Ettinger A.J. Van der Meulen J. Holt K.H. Lim L.E. Sanes J.R. Davidson B.L. Faulkner J.A. Williamson R. Campbell K.P. J. Cell Biol. 1998; 142: 1461-1471Crossref PubMed Scopus (311) Google Scholar, 21Cote P.D. Moukhles H. Lindenbaum M. Carbonetto S. Nat. Genet. 1999; 23: 338-342Crossref PubMed Scopus (201) Google Scholar). 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. 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. As an immediate test of these ideas, it is worth re-examining the single instance where ablation of a dystrophin complex constituent (α-dystrobrevin) results in muscular dystrophy with minimal apparent sarcolemmal damage (18Grady R.M. Grange R.W. Lau K.S. Maimone M.M. Nichol M.C. Stull J.T. Sanes J.R. Nature Cell Biol. 1999; 1: 215-220Crossref PubMed Scopus (283) Google Scholar). When compared with dystrophin-deficientmdx mice, the results with α-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 α-dystrobrevin (and the dystrophin complex) may play a non-mechanical and perhaps signaling role in striated muscle (18Grady R.M. Grange R.W. Lau K.S. Maimone M.M. Nichol M.C. Stull J.T. Sanes J.R. Nature Cell Biol. 1999; 1: 215-220Crossref PubMed Scopus (283) Google Scholar). However, no defect in muscle cell signaling has been identified that can account for the dystrophic phenotype observed in α-dystrobrevin −/− muscle. Furthermore, several two-hybrid screens seeking to reveal candidate signaling molecules regulated by α-dystrobrevin have instead identified several novel intermediate filament proteins as α-dystrobrevin interactors (22Newey S.E. Howman E.V. Ponting C.P. Benson M.A. Nawrotzki R. Loh N.Y. Davies K.E. Blake D.J. J. Biol. Chem. 2001; 276: 6645-6655Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 23Benson M.A. Newey S.E. Martin-Rendon E. Hawkes R. Blake D.J. J. Biol. Chem. 2001; 276: 24232-24241Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar, 24Mizuno Y. Thompson T.G. Guyon J.R. Lidov H.G. Brosius M. Imamura M. Ozawa E. Watkins S.C. Kunkel L.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6156-6161Crossref PubMed Scopus (136) Google Scholar). Two of these proteins, synemin (24Mizuno Y. Thompson T.G. Guyon J.R. Lidov H.G. Brosius M. Imamura M. Ozawa E. Watkins S.C. Kunkel L.M. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6156-6161Crossref PubMed Scopus (136) Google Scholar) and syncoilin (25Poon E. Howman E.V. Newey S.E. Davies K.E. J. Biol. Chem. 2002; 277: 3433-3439Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), also interact with desmin. Striated muscle of mice lacking desmin exhibits numerous structural and functional abnormalities (26Milner D.J. Weitzer G. Tran D. Bradley A. Capetanaki Y. J. Cell Biol. 1996; 134: 1255-1270Crossref PubMed Scopus (438) Google Scholar, 27Li Z. Mericskay M. Agbulut O. Butler-Browne G. Carlsson L. Thornell L.E. Babinet C. Paulin D. J. Cell Biol. 1997; 139: 129-144Crossref PubMed Scopus (300) Google Scholar). Most notably, desmin −/− muscle is weak (27Li Z. Mericskay M. Agbulut O. Butler-Browne G. Carlsson L. Thornell L.E. Babinet C. Paulin D. J. Cell Biol. 1997; 139: 129-144Crossref PubMed Scopus (300) Google Scholar, 28Sam M. Shah S. Friden J. Milner D.J. Capetanaki Y. Lieber R.L. Am. J. Physiol. 2000; 279: C1116-C1122Crossref PubMed Google Scholar, 29Wieneke S. Stehle R. Li Z. Jockusch H. Biochem. Biophys. Res. Commun. 2000; 278: 419-425Crossref PubMed Scopus (23) Google Scholar) but shows no force drop after eccentric contraction (28Sam M. Shah S. Friden J. Milner D.J. Capetanaki Y. Lieber R.L. Am. J. Physiol. 2000; 279: C1116-C1122Crossref PubMed Google Scholar, 29Wieneke S. Stehle R. Li Z. Jockusch H. Biochem. Biophys. Res. Commun. 2000; 278: 419-425Crossref PubMed Scopus (23) Google Scholar). Although explicit tests of increased sarcolemmal permeability have not been reported for desmin-null muscle, the absence of force drop with eccentric contraction (28Sam M. Shah S. Friden J. Milner D.J. Capetanaki Y. Lieber R.L. Am. J. Physiol. 2000; 279: C1116-C1122Crossref PubMed Google Scholar, 29Wieneke S. Stehle R. Li Z. Jockusch H. Biochem. Biophys. Res. Commun. 2000; 278: 419-425Crossref PubMed Scopus (23) Google Scholar) suggests these mice may experience little membrane disruption compared with mdx mice exhibiting large force drops correlating strongly with increased sarcolemmal permeability (14Petrof B.J. Shrager J.B. Stedman H.H. Kelly A.M. Sweeney H.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3710-3714Crossref PubMed Scopus (1184) Google Scholar,15Moens P. Baatsen P.H. Marechal G. J. Muscle Res. Cell Motil. 1993; 14: 446-451Crossref PubMed Scopus (265) Google Scholar). Lateral force transmission is, however, greatly diminished in desmin-null muscle (30Boriek A.M. Capetanaki Y. Hwang W. Officer T. Badshah M. Rodarte J. Tidball J.G. Am. J. Physiol. 2001; 280: C46-C52Crossref PubMed Google Scholar). Taken together, these results suggest that α-dystrobrevin may participate in lateral force transmission through the costamere by coupling the intermediate filament cytoskeleton with the dystrophin complex. If dystrophin, α-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 α-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 α-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 (31Wehling M. Spencer M.J. Tidball J.G. J. Cell Biol. 2001; 155: 123-131Crossref PubMed Scopus (431) Google Scholar) observed restoration of nitric oxide (NO) 1The abbreviations used are: NOnitric oxideNFATnuclear factor of activated T cellsSAPKstress-activated protein kinaseJNKc-Jun N-terminal kinase 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 mdxmuscle. 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 ofmdx muscle (14Petrof B.J. Shrager J.B. Stedman H.H. Kelly A.M. Sweeney H.L. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 3710-3714Crossref PubMed Scopus (1184) Google Scholar, 15Moens P. Baatsen P.H. Marechal G. J. Muscle Res. Cell Motil. 1993; 14: 446-451Crossref PubMed Scopus (265) Google Scholar) 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 (32Tidball J.G. Spencer M.J. Wehling M. Lavergne E. J. Biol. Chem. 1999; 274: 33155-33160Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar) and others (33Chaubourt E. Voisin V. Fossier P. Baux G. Israel M. De La P.S. J. Physiol. (Paris). 2002; 96: 43-52Crossref PubMed Scopus (28) Google Scholar) 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 (34Tinsley J. Deconinck N. Fisher R. Kahn D. Phelps S. Gillis J.M. Davies K. Nature Med. 1998; 4: 1441-1444Crossref PubMed Scopus (485) Google Scholar), including strong coupling between costameric actin and the sarcolemma (35Rybakova I.N. Patel J.R. Davies K.E. Yurchenco P.D. Ervasti J.M. Mol. Biol. Cell. 2002; 13: 1512-1521Crossref PubMed Scopus (88) Google Scholar), 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 (36Warner L.E. DelloRusso C. Crawford R.W. Rybakova I.N. Patel J.R. Ervasti J.M. Chamberlain J.S. Hum. Mol. Genet. 2002; 11: 1095-1105Crossref PubMed Scopus (65) Google Scholar) recently assessed whether the retinal isoform of dystrophin, Dp260, could rescue mdxmuscle. Dp260 lacks the N-terminal actin binding domain and spectrin repeats 1–10 but retains the basic middle rod actin binding site (37Amann K.J. Renley B.A. Ervasti J.M. J. Biol. Chem. 1998; 273: 28419-28423Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar). 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 a mechanical defect in the cytoskeleton as the cause of muscular The challenge remains to to and mechanical defects with the loss of costameric proteins. nitric oxide factor of activated T cells protein kinase N-terminal kinase because costameres are mechanical elements of striated muscle does not that are or it was recently shown that the costameric of is in dystrophin-deficient muscle T.G. A.A. Brosius M. M. Lidov H.G. McNally E.M. Watkins S. Kunkel L.M. J. Cell Biol. 2000; PubMed Scopus Google Scholar). study demonstrated of to focal adhesions mechanical stress M. P. D. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Taken together, these results suggest that the dystrophin-deficient costamere may increased mechanical stress and to through studies that mechanical is in costameric protein and In the first (32Tidball J.G. Spencer M.J. Wehling M. Lavergne E. J. Biol. Chem. 1999; 274: 33155-33160Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar), it was shown that the costamere constituents and vinculin are in to muscle contraction through a neuronal nitric-oxide synthase a constituent of In the study A.M. L. Am. J. Physiol. 1997; 273: PubMed Google Scholar), cardiac were mechanically by of contraction with a costameric staining for vinculin and β1 was but could be by of the or by of stretch. In the study G. T. J. Cell Biol. 2001; PubMed Scopus Google Scholar), the pattern of several costameric proteins and was shown to dramatically in skeletal muscle after 3 of The costamere by could be by or of muscle extracellular in the normal costamere in muscle suggesting that coupling between cell of costameres and the extracellular matrix is the results of these studies indicate that costameres are structures to (and and of an role for the costamere/Z-disk axis in the through which mechanical stimuli are by muscle cells and into 2002; Scholar). The to costameres (Fig. in skeletal muscle S. N. A. T. C. L. F. T. J. Cell Biol. 2001; PubMed Scopus Google Scholar) and is dramatically in to passive in T.J. T.J. M. R. M. 2001; PubMed Scopus Google Scholar). Although its costameric binding partners are and mice no obvious muscle in suggest that can of factor of activated T cells and factor factor S. N. A. T. C. L. F. T. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The and are famous for gene expression with striated muscle and type in to several including mechanical stress 2000; PubMed Scopus Google Scholar). was recently to the Z-disk in skeletal muscle but to the specific of Y. Z. J. Cell Biol. 2001; 155: PubMed Scopus Google Scholar). stimuli act in through in the Z-disk R.D. S. H. J. Biol. Chem. 1983; Full Text PDF PubMed Google Scholar). However, the muscles were also undergoing contraction R.D. S. H. J. Biol. Chem. 1983; Full Text PDF PubMed Google Scholar) so it is that the a specific mechanical stress that was to by through its physical association with and (Fig. N. J.A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, N. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). other results G.S. K. P. J. A.M. M.A. Chamberlain J.S. Biol. 2001; 11: Full Text Full Text PDF PubMed Scopus (65) Google Scholar) suggest that of may be in dystrophin-deficient muscle due to increased by the protein kinase The binding of to costameric M. A. G.M. V. P. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) further that the dystrophin complex may participate in signaling through to the kinase of whereas is in cells A. Z. C. Y. J. J.M. J. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus (155) Google Scholar). Thus, it is that of to costameres in dystrophin-deficient muscle T.G. A.A. Brosius M. M. Lidov H.G. McNally E.M. Watkins S. Kunkel L.M. J. Cell Biol. 2000; PubMed Scopus Google Scholar) leads to and of by Finally, it remains to be how stimuli in the of mechanical force may be into one at the between the cytoskeleton and membrane 2002; Scholar), but this seems to at the costamere and within a it has been suggested that physical may reveal new binding sites within a network of interacting proteins that could signaling molecules with their D. E. T. S. Z. B. J. Cell Biol. 2001; PubMed Scopus Google Scholar). In support of this in non-muscle and Y. J. Cell Biol. 2002; PubMed Scopus Google Scholar) recently demonstrated in the array of proteins to cytoskeletal to that were compared with type of is certainly to striated muscle, where it may the costamere/Z-disk axis as a site of and the molecular studies are to reveal integrated within the of muscle.