Membrane Repair Defects in Muscular Dystrophy Are Linked to Altered Interaction between MG53, Caveolin-3, and Dysferlin

Defective membrane repair can contribute to the progression of muscular dystrophy. Although mutations in caveolin-3 (Cav3) and dysferlin are linked to muscular dystrophy in human patients, the molecular mechanism underlying the functional interplay between Cav3 and dysferlin in membrane repair of muscle physiology and disease has not been fully resolved. We recently discovered that mitsugumin 53 (MG53), a muscle-specific TRIM (Tri-partite motif) family protein (TRIM72), contributes to intracellular vesicle trafficking and is an essential component of the membrane repair machinery in striated muscle. Here we show that MG53 interacts with dysferlin and Cav3 to regulate membrane repair in skeletal muscle. MG53 mediates active trafficking of intracellular vesicles to the sarcolemma and is required for movement of dysferlin to sites of cell injury during repair patch formation. Mutations in Cav3 (P104L, R26Q) that cause retention of Cav3 in Golgi apparatus result in aberrant localization of MG53 and dysferlin in a dominant-negative fashion, leading to defective membrane repair. Our data reveal that a molecular complex formed by MG53, dysferlin, and Cav3 is essential for repair of muscle membrane damage and also provide a therapeutic target for treatment of muscular and cardiovascular diseases that are linked to compromised membrane repair. Defective membrane repair can contribute to the progression of muscular dystrophy. Although mutations in caveolin-3 (Cav3) and dysferlin are linked to muscular dystrophy in human patients, the molecular mechanism underlying the functional interplay between Cav3 and dysferlin in membrane repair of muscle physiology and disease has not been fully resolved. We recently discovered that mitsugumin 53 (MG53), a muscle-specific TRIM (Tri-partite motif) family protein (TRIM72), contributes to intracellular vesicle trafficking and is an essential component of the membrane repair machinery in striated muscle. Here we show that MG53 interacts with dysferlin and Cav3 to regulate membrane repair in skeletal muscle. MG53 mediates active trafficking of intracellular vesicles to the sarcolemma and is required for movement of dysferlin to sites of cell injury during repair patch formation. Mutations in Cav3 (P104L, R26Q) that cause retention of Cav3 in Golgi apparatus result in aberrant localization of MG53 and dysferlin in a dominant-negative fashion, leading to defective membrane repair. Our data reveal that a molecular complex formed by MG53, dysferlin, and Cav3 is essential for repair of muscle membrane damage and also provide a therapeutic target for treatment of muscular and cardiovascular diseases that are linked to compromised membrane repair. Membrane recycling and remodeling contribute to multiple cellular functions, including cell fusion events during myogenesis and maintenance of sarcolemma integrity in striated muscle. During the life cycle of striated muscle, membrane repair is a fundamental process in maintaining cellular integrity, as shown by recent studies that link defective membrane repair to the progression of muscular dystrophy (1.McNeil P.L. Kirchhausen T. Nat. Rev. Mol. Cell Biol. 2005; 6: 499-505Crossref PubMed Scopus (325) Google Scholar, 2.Towler M.C. Kaufman S.J. Brodsky F.M. Traffic. 2004; 5: 129-139Crossref PubMed Scopus (39) Google Scholar, 3.Glover L. Brown Jr., R.H. Traffic. 2007; 8: 785-794Crossref PubMed Scopus (126) Google Scholar). Repair of the plasma membrane damage requires recruitment of intracellular vesicles to injury sites (4.Steinhardt R.A. Bi G. Alderton J.M. Science. 1994; 263: 390-393Crossref PubMed Scopus (409) Google Scholar, 5.Miyake K. McNeil P.L. J. Cell Biol. 1995; 131: 1737-1745Crossref PubMed Scopus (178) Google Scholar). One protein that has been linked to membrane repair in skeletal muscle is dysferlin (6.Klinge L. Laval S. Keers S. Haldane F. Straub V. Barresi R. Bushby K. FASEB J. 2007; 21: 1768-1776Crossref PubMed Scopus (74) Google Scholar, 7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar), which is thought to fuse intracellular vesicles to patch the damaged membrane and restore sarcolemmal integrity following muscle injury. Like dysferlin, caveolin-3 (Cav3) 3The abbreviations used are:Cav3caveolin-3MG53mitsugumin 53HAhyaluronidaseGFPgreen fluorescent proteinRFPred fluorescent proteinFDBflexor digitorum brevisCo-IPco-immunoprecipitationWTwild typeDFLdysferlinTRIMtri-partite motif. is a muscle-specific protein, and many mutations in Cav3, including P104L, R26Q, and C71W, have been linked to muscular dystrophy (8.Minetti C. Sotgia F. Bruno C. Scartezzini P. Broda P. Bado M. Masetti E. Mazzocco M. Egeo A. Donati M.A. Volonte D. Galbiati F. Cordone G. Bricarelli F.D. Lisanti M.P. Zara F. Nat. Genet. 1998; 18: 365-368Crossref PubMed Scopus (497) Google Scholar, 9.Galbiati F. Volonte D. Minetti C. Chu J.B. Lisanti M.P. J. Biol. Chem. 1999; 274: 25632-25641Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 10.Smythe G.M. Eby J.C. Disatnik M.H. Rando T.A. J. Cell Sci. 2003; 116: 4739-4749Crossref PubMed Scopus (60) Google Scholar, 11.Fee D.B. So Y.T. Barraza C. Figueroa K.P. Pulst S.M. Muscle Nerve. 2004; 30: 375-378Crossref PubMed Scopus (29) Google Scholar). Despite extensive research efforts on Cav3 and dysferlin (12.Han R. Campbell K.P. Curr. Opin. Cell Biol. 2007; 19: 409-416Crossref PubMed Scopus (205) Google Scholar, 13.Galbiati F. Razani B. Lisanti M.P. Trends Mol. Med. 2001; 7: 435-441Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 14.Han R. Bansal D. Miyake K. Muniz V.P. Weiss R.M. McNeil P.L. Campbell K.P. J. Clin. Investig. 2007; 117: 1805-1813Crossref PubMed Scopus (137) Google Scholar), the molecular function of these two proteins in membrane repair in muscle physiology and dystrophy have not been fully defined. caveolin-3 mitsugumin 53 hyaluronidase green fluorescent protein red fluorescent protein flexor digitorum brevis co-immunoprecipitation wild type dysferlin tri-partite motif. Animal model studies reveal that either loss or gain of Cav3 function both result in dystrophic phenotypes in skeletal muscle (15.Galbiati F. Volonte D. Chu J.B. Li M. Fine S.W. Fu M. Bermudez J. Pedemonte M. Weidenheim K.M. Pestell R.G. Minetti C. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 9689-9694Crossref PubMed Scopus (132) Google Scholar, 16.Hagiwara Y. Sasaoka T. Araishi K. Imamura M. Yorifuji H. Nonaka I. Ozawa E. Kikuchi T. Hum. Mol. Genet. 2000; 9: 3047-3054Crossref PubMed Scopus (145) Google Scholar), suggesting that associated cellular components may be involved in the etiology of Cav3-related dystrophy. Although the discovery of dysferlin highlights the importance of membrane repair in the etiology of muscular dystrophy, dysferlin itself does not appear to participate in recruitment of intracellular vesicles because dysferlin−/− muscle retains accumulation of vesicles near membrane damage sites (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar). This indicates that proteins other than dysferlin are required for nucleation of intracellular vesicles at the sites of acute membrane damage. Recently, we discovered that MG53, a muscle-specific TRIM family protein (TRIM72), is an essential component of the acute membrane repair machinery. MG53 acts as a sensor of oxidation to nucleate recruitment of intracellular vesicles to the injury site for membrane patch formation (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). We also found that MG53 can regulate membrane budding and exocytosis in muscle cells, and this membrane-recycling function of MG53 can be modulated through a functional interaction with Cav3 (18.Cai C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Here we present evidence that MG53 interacts with dysferlin to facilitate intracellular vesicle trafficking during repair of acute membrane damage. In addition, we show that transgenic overexpression of P104L-Cav3 in striated muscle produces defects in membrane repair that are linked to altered subcellular distribution of MG53 and dysferlin. Our results suggest that altered MG53 localization can be used as a marker for muscular dystrophy involving reduced sarcolemmal membrane repair capacity due to Cav3 mutation, and potentially, in other forms of dystrophy as well. C2C12 murine myoblast cell line was purchased from the American Type Culture Collection (Manassas, VA). Cells were grown in a humidified environment at 37 °C and 5% CO2 in Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin. C2C12 myoblasts were grown to confluence and switched to Dulbecco's modified Eagle's medium containing 2% horse serum to induce serum withdrawal differentiation. Primary myoblasts were derived from wild-type (WT) or mg53−/− neonatal mouse pups using established techniques. For transient transfections, C2C12 myoblasts were plated at 70% confluence in glass bottom and using Cells were by cell at or at the for and of MG53 were (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar, C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Cav3 were using from mouse skeletal muscle. fusion were by Cav3 using the and Cav3 P104L, R26Q, and C71W, were by the in using the J.K. Ma J. J. Cell 2005; PubMed Scopus Google Scholar). fusion was by the Cav3 the of containing the and the fusion was by the mouse MG53 the of containing the was a from Bushby S. Laval Bushby K. R.G. Hum. Mol. Genet. PubMed Scopus Google Scholar). was using techniques. In C2C12 were and with modified supplemented with For or of protein was on was used for co-immunoprecipitation studies of MG53, dysferlin, and C2C12 with and were in of modified For of was with of or of cell was with of mouse were by protein during a by with studies with the skeletal muscle were as in (18.Cai C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). For in of skeletal muscle with or an of of hyaluronidase was the flexor digitorum brevis muscle of wild-type of in was the to of were through the mouse to of of a 100 at S. L. J. G. G. E. J. Proc. Natl. Acad. Sci. U. S. A. 2007; PubMed Scopus Google Scholar). were to from for P104L-Cav3 transgenic were as Y. H. A. H. T. S. S. K. T. Hum. Mol. Genet. 2001; PubMed Google Scholar), and mg53−/− were as (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar, M. Komazaki S. N. Y. T. M. Takeshima H. J. Cell Biol. 1999; PubMed Scopus Google Scholar). For of muscle mg53−/− P104L-Cav3 transgenic wild-type and with or were by and were in a containing were for at 37 °C in supplemented with type were in and were by through a of with N. Brotto M. Komazaki S. Pan Z. Zhao X. T. J. Takeshima H. Ma J. J. Cell Biol. PubMed Scopus Google Scholar). Membrane repair capacity was using established (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar, U. V. McNeil P.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). membrane damage was to using a on a to a at for cell or was to the were at and the of or at the site of the damage was using the (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). cell was used to intracellular trafficking of fluorescent fusion C2C12 or mg53−/− were on glass bottom and using a with a at For C2C12 were with at °C for or were Cells were and or were as the For cell of membrane C2C12 myoblasts or mg53−/− were by the of a to a were using a as defective membrane repair may the progression of muscular dystrophy to mutations in Cav3, we the membrane repair capacity of transgenic that P104L-Cav3 Y. H. A. H. T. S. S. K. T. Hum. Mol. Genet. 2001; PubMed Google Scholar, Y. H. M. K. H. Y. T. S. I. Y. Hum. Mol. Genet. 2004; PubMed Scopus Google Scholar). muscle from the P104L-Cav3 defective membrane repair following injury of the sarcolemma to with the dysferlin−/− (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google and mg53−/− MG53 is a TRIM family protein in striated muscle, which as a sensor of oxidation to nucleate the of the acute membrane repair machinery in skeletal muscle (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). a mg53−/− muscular associated with defective membrane repair and a with the P104L-Cav3 transgenic show that of both MG53 and dysferlin in P104L-Cav3 muscle, the of Cav3 or dysferlin in mg53−/− muscle indicates that the of MG53 and dysferlin in the P104L-Cav3 muscle with muscle that MG53 membrane localization in muscle that is altered in muscle because MG53 in the of muscle of MG53 and dysferlin may a to the defective membrane repair in P104L-Cav3 muscle, altered MG53 localization may a molecular for the defective membrane repair in Cav3-related muscular dystrophy. with Cav3, MG53 and dysferlin are muscle-specific proteins is associated with myogenesis (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar, C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In C2C12 at the myoblast not of these the of is following of C2C12 myoblasts of MG53, Cav3, and dysferlin from C2C12 myoblast a for functional co-immunoprecipitation we that MG53, dysferlin, and Cav3 may a protein complex by with in C2C12 myoblast interaction between MG53, Cav3, and dysferlin is also with proteins in mouse skeletal muscle also (18.Cai C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Our studies that MG53 interacts with to with intracellular vesicles that trafficking to and fusion with sarcolemmal an process involved in the membrane repair function of MG53 (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). studies that the membrane-recycling is a functional interaction with Cav3 (18.Cai C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). the of Cav3 interaction with MG53 in membrane we cell of in C2C12 myoblasts either Cav3 or P104L-Cav3 following injury with a injury of the cell to of the injury sites to a membrane repair Although of Cav3 does not have a on and P104L-Cav3 the membrane repair function of MG53, as by of and of following membrane damage and Although overexpression of Cav3 membrane to the P104L-Cav3 MG53 to injury sites compromised vesicle may provide a for the reduced membrane repair capacity in P104L-Cav3 of P104L-Cav3 produces defective membrane repair in skeletal muscle. muscle from were by in to for transient of and that were by that to the sarcolemmal a of intracellular retention of the Cav3 of defects in membrane repair capacity in is following with of skeletal muscle or or on the green are for for from with shown in the MG53 and P104L-Cav3 in C2C12 interaction on that to the plasma membrane in to intracellular vesicles is in the Golgi as by F. Volonte D. Minetti C. Chu J.B. Lisanti M.P. J. Biol. Chem. 1999; 274: 25632-25641Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, S. Laval Bushby K. R.G. Hum. Mol. Genet. PubMed Scopus Google of P104L-Cav3 in the Golgi has a on the subcellular localization of for C2C12 with Cav3 sarcolemma and localization of a of in the Golgi apparatus of C2C12 P104L-Cav3 is by in C2C12 myoblast with transient of and studies that P104L-Cav3 produces defective MG53 localization to the Golgi that may the defective membrane repair capacity in muscle membrane repair defects with the P104L-Cav3 muscle may a of P104L-Cav3 on the subcellular distribution of MG53 or may other in the muscle membrane due to transgenic of the the acute of P104L-Cav3 on membrane repair in skeletal muscle, we used of containing or the of in studies (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar), of be in skeletal muscle with this shown in in skeletal muscle to the sarcolemmal membrane localization from the sarcolemmal membrane with the intracellular retention in of on membrane repair was by the of following injury. Although overexpression of produces with defects in membrane repair are in as by the of following injury results that P104L-Cav3 has a dominant-negative on both MG53 and membrane repair in skeletal muscle. dominant-negative of P104L-Cav3 on injury to the sarcolemmal membrane to two other Cav3 mutations linked to muscular dystrophy. Cav3 that results in aberrant MG53 localization to Golgi D.B. So Y.T. Barraza C. Figueroa K.P. Pulst S.M. Muscle Nerve. 2004; 30: 375-378Crossref PubMed Scopus (29) Google also produces defects in membrane repair in skeletal muscle a Cav3 that does not MG53 distribution has on membrane repair shown in the subcellular distribution of in C2C12 myoblasts or is to that with the wild-type of with the does not cause retention of MG53 at the Golgi apparatus that with the P104L-Cav3 transient overexpression of in the skeletal muscle does not appear to the membrane repair function following injury because is with the of the that are with either or data suggest that altered subcellular localization of MG53 in with Cav3 may be linked to the defective membrane repair capacity in muscular dystrophy. retention of MG53 in the Golgi by P104L-Cav3 and in this is to a for dysferlin S. Laval Bushby K. R.G. Hum. Mol. Genet. PubMed Scopus Google Scholar). the interaction between MG53, Cav3, and dysferlin we MG53 is involved in dysferlin Bansal (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google that dysferlin is involved in repair of the sarcolemma in skeletal dysferlin itself does not appear to participate in recruitment of intracellular vesicles because dysferlin−/− muscle retains accumulation of vesicles near membrane damage in C2C12 myoblasts that not MG53 or dysferlin to intracellular vesicles to be to cell injury as is recruitment of vesicle the injury site by and MG53 the membrane repair function of dysferlin, we MG53 with in C2C12 MG53, we active fusion and trafficking of vesicles the plasma membrane in to acute membrane damage and We used to the functional between MG53 and dysferlin in the process of acute membrane repair. shown in of green is in C2C12 myoblasts vesicles in myoblasts appear to be as of is during the of the to of trafficking the injury site is with of MG53 or in C2C12 that MG53 vesicle is essential for membrane and maintenance of cellular integrity because mg53−/− are defective in membrane repair and injury by (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). in mg53−/− repair is to MG53 because MG53 can this in mg53−/− dysferlin as be MG53 were required for dysferlin trafficking to injury sites to function in membrane for MG53 in the defective trafficking of dysferlin associated with Cav3 is in mg53−/− myoblast in mg53−/− membrane in to intracellular vesicle distribution which is with the studies of Bansal (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google and (6.Klinge L. Laval S. Keers S. Haldane F. Straub V. Barresi R. Bushby K. FASEB J. 2007; 21: 1768-1776Crossref PubMed Scopus (74) Google Scholar). with P104L-Cav3 to retention of in intracellular vesicles to studies by S. Laval Bushby K. R.G. Hum. Mol. Genet. PubMed Scopus Google Scholar). are with of MG53 with these a of to the Golgi apparatus suggesting that a functional interaction between MG53, Cav3, and dysferlin and that of the function of of these components can the membrane repair capacity of skeletal muscle. In this we show that a functional interaction between MG53, Cav3, and dysferlin is an of membrane repair in skeletal muscle. Our studies show that Cav3 can regulate MG53 by vesicle trafficking and the of associated with MG53 (18.Cai C. Masumiya H. Weisleder N. Pan Z. Nishi M. Komazaki S. Takeshima H. Ma J. J. Biol. Chem. 2009; 284: 3314-3322Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). the functional interaction between MG53 and Cav3, the of on dysferlin to the sarcolemma membrane S. Laval Bushby K. R.G. Hum. Mol. Genet. PubMed Scopus Google Scholar, Laval Bushby K. R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (74) Google are by the of We found that MG53 interacts with dysferlin to facilitate membrane with MG53 of dysferlin by a nucleation mechanism to intracellular vesicles the acute cell injury sites (17.Cai C. Masumiya H. Weisleder N. Matsuda N. Nishi M. Hwang M. Ko J.K. Lin P. Thornton A. Zhao X. Pan Z. Komazaki S. Brotto M. Takeshima H. Ma J. Nat. Cell Biol. 2009; 11: 56-64Crossref PubMed Scopus (346) Google Scholar). altered MG53 localization can be used as a marker for muscular dystrophy involving reduced sarcolemmal membrane repair capacity due to Cav3 mutation, and potentially, in other forms of dystrophy as well. Our results that MG53, Cav3, and dysferlin may a molecular complex that in membrane repair in striated We that of the function of of these components can the subcellular localization and membrane repair function of the other mutations of either Cav3 or dysferlin can to reduced membrane repair capacity and the of muscular dystrophy in L. Brown Jr., R.H. Traffic. 2007; 8: 785-794Crossref PubMed Scopus (126) Google Scholar, Laval Bushby K. R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (74) Google Scholar, M. Straub V. Bushby K. H. Curr. Opin. 21: PubMed Scopus Google Scholar). is also that molecular between MG53, dysferlin, and caveolin-3 may the integrity of the sarcolemmal through with the maintenance of the and is for the integrity and repair capacity of muscle results that the function of these proteins in membrane repair may on MG53, is that mutations in the that with muscular dystrophy or be found in the of in MG53 of the functional interplay between MG53, Cav3, and dysferlin in muscle physiology and to this dysferlin has been to participate in maintenance of muscle membrane integrity (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar, D. Campbell K.P. Trends Cell Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). was that dysferlin can function as a to vesicles to a membrane repair This was on that dysferlin at the injury sites of muscle and the muscular dystrophy that in dysferlin (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar). the by Bansal (7.Bansal D. Miyake K. Vogel S.S. Groh S. Chen C.C. Williamson R. McNeil P.L. Campbell K.P. Nature. 2003; 423: 168-172Crossref PubMed Scopus (779) Google Scholar), has been that dysferlin itself can facilitate the of vesicles associated with acute membrane damage. dysferlin−/− muscle the capacity for vesicle to damage sites on the This that dysferlin may participate in the proteins other than dysferlin are required for nucleation of intracellular vesicles the acute injury Our data show that MG53 can with dysferlin to facilitate repair of acute membrane damage. studies have shown that both the and the function Cav3 result in muscular dystrophy, in an (8.Minetti C. Sotgia F. Bruno C. Scartezzini P. Broda P. Bado M. Masetti E. Mazzocco M. Egeo A. Donati M.A. Volonte D. Galbiati F. Cordone G. Bricarelli F.D. Lisanti M.P. Zara F. Nat. Genet. 1998; 18: 365-368Crossref PubMed Scopus (497) Google Scholar, E. Lisanti M.P. M. M. Hum. Mol. Genet. 1998; 7: PubMed Scopus Google Scholar, F. Volonte D. Minetti C. Li M. Jr., H. B. Lisanti M.P. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Our of a dominant-negative function for the and mutations Cav3 in membrane repair provide a molecular mechanism for of the of Cav3 mutations in dystrophy to the of Cav3 mutations MG53 is that of the interaction between MG53 and Cav3 have functional on of membrane repair capacity in dystrophic the that the functional interaction between MG53, Cav3, and dysferlin through either or be an therapeutic for muscular dystrophy and other human diseases compromised membrane integrity contributes to cellular For MG53 and Cav3 are both present in muscle in to skeletal muscle. membrane damage contributes to the of during injury or progression of K. Y. T. T. K. T. J. 2004; PubMed Scopus Google Scholar, Chen Lin Lin PubMed Scopus Google Scholar, T. S. M. Z. C. J. Mol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), of of membrane repair be an for research in the muscle and cardiovascular We Chu for in data and and Bushby for the with

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