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Journal of Muscle Research & Cell Motility

, Volume 26, Issue 6–8, pp 409–417 | Cite as

Possible functions of p94 in connectin-mediated signaling pathways in skeletal muscle cells

  • Koichi Ojima
  • Yasuko Ono
  • Shoji Hata
  • Suguru Koyama
  • Naoko Doi
  • Hiroyuki Sorimachi
Article

Abstract

Calpains are intracellular Ca2+-requiring ‘modulator proteases’, which modulate cellular functions by limited and specific proteolysis. p94/calpain3, a skeletal-muscle specific calpain, has been one of the representative calpain species which indicates physiological importance of calpain proteolytic system; a defect of proteolytic activity of p94 causes limb girdle muscular dystrophy type2A (LGMD2A, also called ‘calpainopathy’). Immunohistochemical studies on myofibrils showed that p94 localizes at the Z- and N2-line regions of sarcomeres. It was also identified by the yeast two hybrid studies that p94 binds to the N2A and M-line regions of connectin. Furthermore, genetic studies indicate that p94 is indispensable for skeletal muscles, although its precise functions are still unclear. Interestingly, connectin provides sarcomere not only with elasticity but also with binding sites to various multi-functional proteins such as muscle ankyrin repeat proteins (MARPs), muscle RING finger proteins (MURFs), titin-capping protein (T-cap/telethonin), sarcomeric-α-actinin, p94 etc. Binding sites for these proteins are not randomly placed along connectin but rather accumulated in the Z-, N2-, and/or M-line regions, indicating the existence of ‘signal complexes’ unique to each regions. The concept of these complexes are strongly supported by the facts that mutations of connectin or its binding proteins in these regions severely perturb muscle functions, as in the case of LGMD2A caused by mutations in the p94 gene. Therefore, it is hypothesized that the ‘signal complexes’ in the Z-, N2-, and M-lines modulate muscle cell homeostasis by transducing signals of external stimulations/stresses to trigger appropriate response at various different cellular events such as protein modification and gene expressions. In this article, we performed detailed immunohistochemical analyses of p94 on isolated single myofibers. Together with recent findings about p94, it is suggested that sarcomeric localization of p94, especially its M-line localization, is affected by the combination of cellular contexts such as contractile status of myofibrils, fiber type compositions, sarcomeric maturation, and the composition of the ‘signal complexes’ in each region.

Keywords

Muscular Dystrophy Extensor Digitorum Longus Limb Girdle Muscular Dystrophy Cardiac Ankyrin Repeat Protein PEVK Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Notes

Acknowledgements

We would like to thank Dr Siegfried Labeit and Dr Christian Witt in Universitätsklinikum Mannheim, Dr Carol C. Gregorio in University of Arizona, and Dr Sumiko Kimura in University of Chiba for valuable discussions. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (Cell Cycle) from the Ministry of Education, Science, Sports and Culture, a Grant-in-Aid for Scientific Research and Research Fellowships for Young Scientists from JSPS (the Japan Society for the Promotion of Science), a Research Grant (14B-4) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare, and ‘Ground-based Research Announcement for Space Utilization’ promoted by the Japan Space Forum. This paper is dedicated to the memory of Prof Koscak Maruyama. We all miss him.

References

  1. Baghdiguian S, Martin M, Richard I, Pons F, Astier C, Bourg N, Hay RT, Chemaly R, Halaby G, Loiselet J, Anderson LVB, Munain ALd, Fardeau M, Mangeat P, Beckmann JS, Lefranc G, (1999) Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IB/NF-B pathway in limb-girdle muscular dystrophy type 2A Nat Med 5:503–511PubMedCrossRefGoogle Scholar
  2. Baumeister A, Arber S, Caroni P, (1997) Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis J Cell Biol 139:1231–1242PubMedCrossRefGoogle Scholar
  3. Bischoff R, (1986) Proliferation of muscle satellite cells on intact myofibers in culture Dev Biol 115:129–139PubMedCrossRefGoogle Scholar
  4. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ, (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy Science 294:1704–1708PubMedCrossRefGoogle Scholar
  5. Centner T, Yano J, Kimura E, McElhinny AS, Pelin K, Witt CC, Bang M-L, Trombitas K, Granzier H, Gregorio CC, Sorimachi H, Labeit S, (2001) Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain J Mol Biol 306:717–726PubMedCrossRefGoogle Scholar
  6. Cottin P, Brustis JJ, Poussard S, Elamrani N, Broncard S, Ducastaing A, (1994) Ca2+-dependent proteinases (calpains) and muscle cell differentiation Biochim Biophys Acta 1223:170–178PubMedCrossRefGoogle Scholar
  7. Dai K-S, Liew C-C, (2001) A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain J Biol Chem 276:23992–23999PubMedCrossRefGoogle Scholar
  8. Evarsti J, (2003) Costameres: the Achilles’ heel of Herculean muscle J Biol Chem 278:13591–13594CrossRefGoogle Scholar
  9. Franco SJ, Rodgers MA, Perrin BJ, Han J, Bennin DA, Critchley DR, Huttenlocher A, (2004) Calpain-mediated proteolysis of talin regulates adhesion dynamics Nat Cell Biol 6:977–983PubMedCrossRefGoogle Scholar
  10. Furukawa T, Ono Y, Tsuchiya H, Katayama Y, Bang M-L, Labeit D, Labeit S, Inagaki N, Gregorio CC, (2001) Specific interaction of the potassium channel-subunit minK with the sarcomeric protein T-cap suggests a T-tubule-myofibril linking system J Mol Biol 313:775–784PubMedCrossRefGoogle Scholar
  11. Garvey SM, Rajan C, Lerner AP, Frankel WN, Cox GA, (2002) The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin Genomics 79:146–149PubMedCrossRefGoogle Scholar
  12. Glading A, Lauffenburger DA, Wells A, (2002) Cutting to the chase: calpain proteases in cell motility Trends Cell Biol 12:46–54PubMedCrossRefGoogle Scholar
  13. Goll DE, Thompson VF, Li H, Wei W, Cong J, (2003) The calpain system Physiol Rev 83:731–801PubMedGoogle Scholar
  14. Gotthardt M, Hammer RE, Hubner N, Monti J, Witt CC, McNabb M, Richardson JA, Granzier H, Labeit S, (2003) Conditional expression of mutant titins results in cardiomyopathy with altered sarcomere structure J Biol Chem 278:6059–6065PubMedCrossRefGoogle Scholar
  15. Granzier HL, Labeit S, (2004) The giant protein titin: a major player in myocardial mechanics, signaling and disease Circ Res 94:284–295PubMedCrossRefGoogle Scholar
  16. Gregorio CC, Granzier H, Sorimachi H, Labeit S, (1999) Muscle assembly: a titanic achievement? Curr Opin Cell Biol 11:18–25PubMedCrossRefGoogle Scholar
  17. Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H, Sorimachi H, Labeit S, (1998) The NH2 terminus of titin spans the Z-disc: its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity J Cell Biol 143:1013–1027PubMedCrossRefGoogle Scholar
  18. Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B, (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin Am J Hum Genet 71:492–500PubMedCrossRefGoogle Scholar
  19. Hata S, Sorimachi H, Nakagawa K, Maeda T, Abe K, Suzuki K, (2001) Both the conserved and the unique gene structure of stomach-specific calpains reveal processes of calpain gene evolution J Mol Evol 53:191–203PubMedCrossRefGoogle Scholar
  20. Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC, (2000) Myotilin is mutated in limb girdle muscular dystrophy 1A Hum Mol Genet 9:2141–2147PubMedCrossRefGoogle Scholar
  21. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus Nat Genet 26:163–175PubMedCrossRefGoogle Scholar
  22. Ikeda K, Emoto N, Matsuo M, Yokoyama M, (2003) Molecular identification and characterization of a novel nuclear protein whose expression is up-regulated in insulin-resistant animalsJ Biol Chem 278:3514–3520PubMedCrossRefGoogle Scholar
  23. Jenne DE, Kley RA, Vorgerd M, Schröder JM, Weis J, Reimann H, Albrecht B, Nürnberg P, Thiele H, Müller CR, Meng G, Witt C, Labeit S, (2005) Limb girdle muscular dystrophy in a sibling pair with a homozygous Ser606Leu mutation in the alternatively spliced IS2 region of calpain 3 Biol Chem 386:61–67PubMedCrossRefGoogle Scholar
  24. Kawabata Y, Hata S, Ono Y, Ito Y, Suzuki K, Abe K, Sorimachi H, (2003) Newly identified exons encoding novel variants of p94/calpain 3 are expressed ubiquitously and overlap the -glucosidase C gene FEBS Lett 555:623–630PubMedCrossRefGoogle Scholar
  25. Keira Y, Noguchi S, Minami N, Hayashi YK, Nishino I, (2003) Localization of calpain 3 in human skeletal muscle and its alteration in limb-girdle muscular dystrophy 2A muscle J BioChem (Tokyo) 133:659–664Google Scholar
  26. Kinbara K, Ishiura S, Tomioka S, Sorimachi H, Jeong S-Y, Amano S, Kawasaki H, Kolmerer B, Kimura S, Labeit S, Suzuki K, (1998) Purification of native p94, a muscle-specific calpain, and characterization of its autolysis BioChem J 335:589–596PubMedGoogle Scholar
  27. Kinbara K, Sorimachi H, Ishiura S, Suzuki K, (1997) Muscle-specific calpain, p94, interacts with the extreme C-terminal region of connectin, a unique region flanked by two immunoglobulin C2 motifs Arch BioChem Biophys 342:99–107PubMedCrossRefGoogle Scholar
  28. Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR, (1999) Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis Devlopment 126:4223–4234Google Scholar
  29. Labeit S, Gautel M, Lakey A, Trinick J, (1992) Towards a molecular understanding of titin EMBO J 11:1711–1716PubMedGoogle Scholar
  30. Labeit S, Kolmerer B, (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity Science 270:293–296PubMedGoogle Scholar
  31. Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression FASEB J 18:39–51PubMedCrossRefGoogle Scholar
  32. Ma H, Fukiage C, Azuma M, Shearer TR, (1998) Cloning and expression of mRNA for calpain Lp82 from rat lens: splice variant of p94 Invest Ophthalmol Vis Sci 39:454–461PubMedGoogle Scholar
  33. Maruyama K, (1976) Connectin, an elastic protein from myofibrils J BioChem 80:405–407PubMedGoogle Scholar
  34. McElhinny AS, Kakinuma K, Sorimachi H, Labeit S, Gregorio CC, (2002) Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1 J Cell Biol 157:125–136PubMedCrossRefGoogle Scholar
  35. Miller MK, Bang M-L, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S, (2003) The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules J Mol Biol 333:951–964PubMedCrossRefGoogle Scholar
  36. Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE, (2000) Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin Nat Genet 24:163–166PubMedCrossRefGoogle Scholar
  37. Moyen C, Goudenege S, Poussard S, Sassi AH, Brustis J-J, Cottin P, (2004) Involvement of micro-calpain (CAPN 1) in muscle cell differentiation Inter J BioChem Cell Biol 36:728–743CrossRefGoogle Scholar
  38. Mues A, Ven PFMvd, Young P, Fürst DO, Gautel M, (1998) Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin FEBS Lett 428:111–114PubMedCrossRefGoogle Scholar
  39. Nikawa T, Ishidoh K, Hirasaka K, Ishihara I, Ikemoto M, Kano M,Kominami E, Nonaka I, Ogawa T, Adams GR, Baldwin KM, Yasui N, Kishi K Takeda S. (2004). Skeletal muscle gene expression in space-flown rats FASEB J 18: 522–524PubMedGoogle Scholar
  40. Ohtsuka H, Yajima H, Maruyama K, Kimura S, (1997) Binding of the N-terminal 63 kDa portion of connectin/titin to alpha-actinin as Rev.ealed by the yeast two-hybrid system FEBS Lett 401:65–67PubMedCrossRefGoogle Scholar
  41. Ojima K, Lin ZX, Zhang ZQ, Hijikata T, Holtzer S, Labeit S, Sweeney HL, Holtzer H, (1999) Initiation and maturation of I-Z-I bodies in the growth tips of transfected myotubes J Cell Sci 112:4101–4112PubMedGoogle Scholar
  42. Ojima K, Uezumi A, Miyoshi H, Masuda S, Morita Y, Fukase A, Hattori A, Nakauchi H, Miyagoe-Suzuki Y, Takeda S, (2004) Mac-1(low) early myeloid cells in the bone marrow-derived SP fraction migrate into injured skeletal muscle and participate in muscle regeneration BioChem Biophys Res Commun 321:1050–1061PubMedCrossRefGoogle Scholar
  43. Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K, (1998) Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A J Biol Chem 273:17073–17078PubMedCrossRefGoogle Scholar
  44. Pallavicini A, Kojic S, Bean C, Vainzof M, Salamon M, Levolella C, Bortoletto G, Pacchioni B, Zatz M, Lanfranchi G, Faulkner G, Valle G, (2001) Characterization of human skeletal muscle Ankrd2. BioChem Biophys Res Commun 285:378–386PubMedCrossRefGoogle Scholar
  45. Raynaud F, Carnac G, Marcihac A, Benyamin Y, (2004) m-calpain implication in cell cycle during muscle precursor activation Exp Cell Res 298:48–57PubMedCrossRefGoogle Scholar
  46. Rey MA, Davies PL, (2002) The protease core of the muscle-specific calpain, p94, undergoes Ca2+ dependent intramolecular autolysis FEBS Lett 532:401–406PubMedCrossRefGoogle Scholar
  47. Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C, Hillaire D, Passos-Bueno MR, Zatz M, Tischfield JA, Fardeau M, Jackson CE, Cohen D and Beckmann JS (1995) Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81: 27–40Google Scholar
  48. Saito K, Elce JS, Hamos JE, Nixon RA, (1993) Widespread activation of calcium-activated neutral proteinase (Calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration Pro Natl Acad Sci USA 90:2628–2632CrossRefGoogle Scholar
  49. Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O, (1999) Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy Hum Mol Genet 8:1329–1336PubMedCrossRefGoogle Scholar
  50. Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA, Suzuki K, Labeit S, (1997) Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs J Mol Biol 270:688–695PubMedCrossRefGoogle Scholar
  51. Sorimachi H, Kinbara K, Kimura S, Takahashi M, Ishiura S, Sasagawa N, Sorimachi N, Shimada H, Tagawa K, Maruyama K, Suzuki K, (1995) Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence J Biol Chem 270:31158–31162PubMedCrossRefGoogle Scholar
  52. Sorimachi H, Suzuki K, (2001) The structure of calpain J BioChem 129:653–664PubMedGoogle Scholar
  53. Sorimachi H, Toyama-Sorimachi N, Saido TC, Kawasaki H, Sugita H, Miyasaka M, Arahata K, Ishiura S, Suzuki K, (1993) Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle J Biol Chem 268:10593–10605PubMedGoogle Scholar
  54. Soteriou A, Gamage M, Trinick J, (1993) A survey of interactions made by the giant protein titin J Cell Sci 104:119–123PubMedGoogle Scholar
  55. Spencer MJ, Guyon JR, Sorimachi H, Potts A, Richard I, Herasse M, Chamberlain J, Dalkilic I, Kunkel LM, Beckmann JS, (2002) Stable expression of calpain 3 from a muscle transgene in vivo: immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation Proc Natl Acad Sci U S A 99:8874–8879PubMedCrossRefGoogle Scholar
  56. Suzuki K, Hata S, Kawabata Y, Sorimachi H, (2004) Structure, activation, and Biol.ogy of calpain Diabetes 53:S12–S18PubMedGoogle Scholar
  57. Tompa P, (2002) Intrinsically unstructured proteins Trends BioChem Sci 27:523–533CrossRefGoogle Scholar
  58. Tullio RD, Stifanese R, Salamino F, Pontremoli S, Melloni E, (2003) Characterization of a new p94-like calpain form in human lymphocytes BioChem J 375:689–696PubMedCrossRefGoogle Scholar
  59. Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkila H, Ingo S, Kalimo H, Kaariainen H, Laulumaa V, Paljarvi PL, Rapola J, Reunanen M, Sonninen V, Somer H, (1993) Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients Arch Neurol 50:604–608PubMedGoogle Scholar
  60. Valle G, Faulkner G, Antoni AD, Pacchioni B, Pallavicini A, Pandolfo D, Tiso N, Toppo S, Trevisan S, Lanfranchi G, (1997) Telethonin, a novel sarcomeric protein of heart and skeletal muscle FEBS Lett 415:163–168PubMedCrossRefGoogle Scholar
  61. Wang K, McClure J, Tu A, (1979) Titin: major myofibrillar components of striated muscle Pro Natl Acad Sci USA 76:3698–3702CrossRefGoogle Scholar
  62. Welm AL, Timchenko NA, Ono Y, Sorimachi H, Radomska HS, Tenen DG, Lekstrom-Himes J, Darlington GJ, (2002) C/EBPα Is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells J Biol Chem 277:33848–33856PubMedCrossRefGoogle Scholar
  63. Witt CC, Ono Y, Puschmann E, McNabb M, Wu Y, Gotthardt M, Witt SH, Haak M, Labeit D, Gregorio CC, Sorimachi H, Granzier H, Labeit S, (2004) Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling J Mol Biol 336:145–154PubMedCrossRefGoogle Scholar
  64. Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR, (1997) CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2–5 homeobox gene pathway Development 124:793–804PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Koichi Ojima
    • 1
    • 2
  • Yasuko Ono
    • 1
  • Shoji Hata
    • 1
  • Suguru Koyama
    • 1
    • 3
  • Naoko Doi
    • 1
    • 2
  • Hiroyuki Sorimachi
    • 1
    • 2
  1. 1.Department of Enzymatic Regulation for Cell FunctionThe Metropolitan Institute of Medical Science (Rinshoken)Bunkyo-ku, TokyoJapan
  2. 2.CREST, Japan Science and Technology Agency (JST)KawaguchiJapan
  3. 3.Graduate School of Agricultural and Life SciencesThe University of TokyoBunkyo-ku, TokyoJapan

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