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Desmin and Heart Disease

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Cytoskeleton and Human Disease

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Abstract

Desmin is the major intermediate filament protein in muscle cells and is one of the earliest myogenic markers of skeletal and cardiac muscle differentiation. The muscle-specific expression of desmin is regulated by a unique combination of transcriptional and epigenetic controls. Desmin protein functions in the maintenance of myofibril organization and structural and functional integrity of muscle. Loss-of-function studies in mice suggest an additional role for desmin in mitochondrial distribution, morphology, and function. Mutations in desmin or its chaperone protein αB-crystallin are associated with myopathy of skeletal and cardiac muscle. The “desminopathies” are characterized by the accumulation of intracellular desmin-positive protein inclusions and gain of function transgenic models show that mutations in desmin and αB-crystallin are autosomal dominant and sufficient to recapitulate the most important aspects of the human disease. Further study of these models has revealed that a large number of pathological processes are involved in disease development, which may provide starting points for targeting future therapeutic interventions.

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References

  1. Ishikawa H, Bischoff R, Holtzer H (1968) Mitosis and intermediate-sized filaments in developing skeletal muscle. J Cell Biol 38:538–555

    Article  PubMed  CAS  Google Scholar 

  2. Lazarides E, Hubbard BD (1976) Immunological characterization of the subunit of the 100Å filaments from muscle cells. Proc Natl Acad Sci USA 73:4344–4348

    Article  PubMed  CAS  Google Scholar 

  3. Small JV, Sobieszek A (1977) Studies on the function and composition of the 10-NM (100Å) filaments of vertebrate smooth muscle. J Cell Sci 23:243–268

    PubMed  CAS  Google Scholar 

  4. Capetanaki YG, Ngai J, Lazarides E (1984) Characterization and regulation in the expression of a gene coding for the intermediate filament protein desmin. Proc Natl Acad Sci USA 81:6909–6913

    Article  PubMed  CAS  Google Scholar 

  5. Li ZL, Lilienbaum A, Butler-Browne G, Paulin D (1989) Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development. Gene 78:243–254

    Article  PubMed  CAS  Google Scholar 

  6. Viegas-Pequignot E, Li ZL, Dutrillaux B, Apiou F, Paulin D (1989) Assignment of human desmin gene to band 2q35 by nonradioactive in situ hybridization. Hum Genet 83:33–36

    Article  PubMed  CAS  Google Scholar 

  7. Costa ML, Escaleira R, Cataldo A, Oliveira F, Mermelstein CS (2004) Desmin: molecular interactions and putative functions of the muscle intermediate filament protein. Braz J Med Biol Res 37:1819–1830

    Article  PubMed  CAS  Google Scholar 

  8. Li ZL, Paulin D (1991) High level desmin expression depends on a muscle-specific enhancer. J Biol Chem 266:6562–6570

    PubMed  CAS  Google Scholar 

  9. Li Z, Paulin D (1993) Different factors interact with myoblast-specific and myotube-specific enhancer regions of the human desmin gene. J Biol Chem 268:10403–10415

    PubMed  CAS  Google Scholar 

  10. Li Z, Marchand P, Humbert J, Babinet C, Paulin D (1993) Desmin sequence elements regulating skeletal muscle-specific expression in transgenic mice. Development 117:947–959

    PubMed  CAS  Google Scholar 

  11. Kuisk IR, Li H, Tran D, Capetanaki Y (1996) A single MEF2 site governs desmin transcription in both heart and skeletal muscle during mouse embryogenesis. Dev Biol 174:1–13

    Article  PubMed  CAS  Google Scholar 

  12. Tam JL, Triantaphyllopoulos K, Todd H, Raguz S, de Wit T, Morgan JE, Partridge TA, Makrinou E, Grosveld F, Antoniou M (2006) The human desmin locus: gene organization and LCR-mediated transcriptional control. Genomics 87:733–746

    Article  PubMed  CAS  Google Scholar 

  13. Lindahl Allen M, Koch CM, Clelland GK, Dunham I, Antoniou M (2009) DNA methylation-histone modification relationships across the desmin locus in human primary cells. BMC Mol Biol 10:51

    Article  PubMed  Google Scholar 

  14. Schaart G, Viebahn C, Langmann W, Ramaekers F (1989) Desmin and titin expression in early postimplantation mouse embryos. Development 107:585–596

    PubMed  CAS  Google Scholar 

  15. Furst DO, Osborn M, Weber K (1989) Myogenesis in the mouse embryo: differential onset of expression of myogenic proteins and the involvement of titin in myofibril assembly. J Cell Biol 109:517–527

    Article  PubMed  CAS  Google Scholar 

  16. Babai F, Musevi-Aghdam J, Schurch W, Royal A, Gabbiani G (1990) Coexpression of alpha-sarcomeric actin, alpha-smooth muscle actin and desmin during myogenesis in rat and mouse embryos I. Skeletal muscle. Differentiation 44:132–142

    Article  PubMed  CAS  Google Scholar 

  17. Hill CS, Duran S, Lin ZX, Weber K, Holtzer H (1986) Titin and myosin, but not desmin, are linked during myofibrillogenesis in postmitotic mononucleated myoblasts. J Cell Biol 103:2185–2196

    Article  PubMed  CAS  Google Scholar 

  18. Geisler N, Weber K (1988) Phosphorylation of desmin in vitro inhibits formation of intermediate filaments; identification of three kinase A sites in the aminoterminal head domain. EMBO J 7:15–20

    PubMed  CAS  Google Scholar 

  19. Kaufmann E, Weber K, Geisler N (1985) Intermediate filament forming ability of desmin derivatives lacking either the amino-terminal 67 or the carboxy-terminal 27 residues. J Mol Biol 185:733–742

    Article  PubMed  CAS  Google Scholar 

  20. Herrmann H, Aebi U (2000) Intermediate filaments and their associates: multi-talented structural elements specifying cytoarchitecture and cytodynamics. Curr Opin Cell Biol 12:79–90

    Article  PubMed  CAS  Google Scholar 

  21. Strelkov SV, Herrmann H, Aebi U (2003) Molecular architecture of intermediate filaments. Bioessays 25:243–251

    Article  PubMed  CAS  Google Scholar 

  22. Ervasti JM (2003) Costameres: the Achilles’ heel of Herculean muscle. J Biol Chem 278:13591–13594

    Article  PubMed  CAS  Google Scholar 

  23. Tidball JG (1992) Desmin at myotendinous junctions. Exp Cell Res 199:206–212

    Article  PubMed  CAS  Google Scholar 

  24. Tokuyasu KT, Dutton AH, Singer SJ (1983) Immunoelectron microscopic studies of desmin (skeletin) localization and intermediate filament organization in chicken cardiac muscle. J Cell Biol 96:1736–1742

    Article  PubMed  CAS  Google Scholar 

  25. Fuseler JW, Shay JW (1982) The association of desmin with the developing myofibrils of cultured embryonic rat heart myocytes. Dev Biol 91:448–457

    Article  PubMed  CAS  Google Scholar 

  26. Tokuyasu KT, Dutton AH, Singer SJ (1983) Immunoelectron microscopic studies of desmin (skeletin) localization and intermediate filament organization in chicken skeletal muscle. J Cell Biol 96:1727–1735

    Article  PubMed  CAS  Google Scholar 

  27. Tokuyasu KT, Maher PA, Singer SJ (1985) Distributions of vimentin and desmin in developing chick myotubes in vivo. II. Immunoelectron microscopic study. J Cell Biol 100:1157–1166

    Article  PubMed  CAS  Google Scholar 

  28. Toivola DM, Tao GZ, Habtezion A, Liao J, Omary MB (2005) Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments. Trends Cell Biol 15:608–617

    Article  PubMed  CAS  Google Scholar 

  29. Huang X, Li J, Foster D, Lemanski SL, Dube DK, Zhang C, Lemanski LF (2002) Protein kinase C-mediated desmin phosphorylation is related to myofibril disarray in cardiomyopathic hamster heart. Exp Biol Med (Maywood) 227:1039–1046

    CAS  Google Scholar 

  30. Inada H, Togashi H, Nakamura Y, Kaibuchi K, Nagata K, Inagaki M (1999) Balance between activities of Rho kinase and type 1 protein phosphatase modulates turnover of phosphorylation and dynamics of desmin/vimentin filaments. J Biol Chem 274:34932–34939

    Article  PubMed  CAS  Google Scholar 

  31. Inagaki M, Gonda Y, Matsuyama M, Nishizawa K, Nishi Y, Sato C (1988) Intermediate filament reconstitution in vitro. The role of phosphorylation on the assembly-disassembly of desmin. J Biol Chem 263:5970–5978

    PubMed  CAS  Google Scholar 

  32. Kitamura S, Ando S, Shibata M, Tanabe K, Sato C, Inagaki M (1989) Protein kinase C phosphorylation of desmin at four serine residues within the non-alpha-helical head domain. J Biol Chem 264:5674–5678

    PubMed  CAS  Google Scholar 

  33. Ohtakara K, Inada H, Goto H, Taki W, Manser E, Lim L, Izawa I, Inagaki M (2000) p21-activated kinase PAK phosphorylates desmin at sites different from those for Rho-associated kinase. Biochem Biophys Res Commun 272:712–716

    Article  PubMed  CAS  Google Scholar 

  34. Inada H, Goto H, Tanabe K, Nishi Y, Kaibuchi K, Inagaki M (1998) Rho-associated kinase phosphorylates desmin, the myogenic intermediate filament protein, at unique amino-terminal sites. Biochem Biophys Res Commun 253:21–25

    Article  PubMed  CAS  Google Scholar 

  35. Kawajiri A, Yasui Y, Goto H, Tatsuka M, Takahashi M, Nagata K, Inagaki M (2003) Functional significance of the specific sites phosphorylated in desmin at cleavage furrow: Aurora-B may phosphorylate and regulate type III intermediate filaments during cytokinesis coordinatedly with Rho-kinase. Mol Biol Cell 14:1489–1500

    Article  PubMed  CAS  Google Scholar 

  36. Kusubata M, Matsuoka Y, Tsujimura K, Ito H, Ando S, Kamijo M, Yasuda H, Ohba Y, Okumura E, Kishimoto T et al (1993) Cdc2 kinase phosphorylation of desmin at three serine/threonine residues in the amino-terminal head domain. Biochem Biophys Res Commun 190:927–934

    Article  PubMed  CAS  Google Scholar 

  37. Thornell LE, Eriksson A (1981) Filament systems in the Purkinje fibers of the heart. Am J Physiol 241:H291–H305

    PubMed  CAS  Google Scholar 

  38. Goebel HH (1995) Desmin-related neuromuscular disorders. Muscle Nerve 18:1306–1320

    Article  PubMed  CAS  Google Scholar 

  39. Goldfarb LG, Park KY, Cervenakova L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC (1998) Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet 19:402–403

    Article  PubMed  CAS  Google Scholar 

  40. Munoz-Marmol AM, Strasser G, Isamat M, Coulombe PA, Yang Y, Roca X, Vela E, Mate JL, Coll J, Fernandez-Figueras MT, Navas-Palacios JJ, Ariza A, Fuchs E (1998) A dysfunctional desmin mutation in a patient with severe generalized myopathy. Proc Natl Acad Sci USA 95:11312–11317

    Article  PubMed  CAS  Google Scholar 

  41. Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D, Fardeau M (1998) A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet 20:92–95

    Article  PubMed  CAS  Google Scholar 

  42. Fardeau M, Vicart P, Caron A, Chateau D, Chevallay M, Collin H, Chapon F, Duboc D, Eymard B, Tome FM, Dupret JM, Paulin D, Guicheney P (2000) Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material with mutation of the alphaB-cristallin gene. Rev Neurol (Paris) 156:497–504

    PubMed  CAS  Google Scholar 

  43. Sanbe A, Osinska H, Saffitz JE, Glabe CG, Kayed R, Maloyan A, Robbins J (2004) Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc Natl Acad Sci USA 101:10132–10136

    Article  PubMed  CAS  Google Scholar 

  44. Wang X, Osinska H, Klevitsky R, Gerdes AM, Nieman M, Lorenz J, Hewett T, Robbins J (2001a) Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res 89:84–91

    Article  CAS  Google Scholar 

  45. Wang X, Osinska H, Dorn GW II, Nieman M, Lorenz JN, Gerdes AM, Witt S, Kimball T, Gulick J, Robbins J (2001b) Mouse model of desmin-related cardiomyopathy. Circulation 103:2402–2407

    Article  CAS  Google Scholar 

  46. Dalakas MC, Dagvadorj A, Goudeau B, Park KY, Takeda K, Simon-Casteras M, Vasconcelos O, Sambuughin N, Shatunov A, Nagle JW, Sivakumar K, Vicart P, Goldfarb LG (2003) Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations. Neuromuscul Disord 13:252–258

    Article  PubMed  Google Scholar 

  47. Dalakas MC, Park KY, Semino-Mora C, Lee HS, Sivakumar K, Goldfarb LG (2000) Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med 342:770–780

    Article  PubMed  CAS  Google Scholar 

  48. Goldfarb LG, Dalakas MC (2009) Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease. J Clin Invest 119:1806–1813

    Article  PubMed  CAS  Google Scholar 

  49. Goldfarb LG, Olive M, Vicart P, Goebel HH (2008) Intermediate filament diseases: desminopathy. Adv Exp Med Biol 642:131–164

    Article  PubMed  CAS  Google Scholar 

  50. Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (1996) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin. J Cell Biol 134:1255–1270

    Article  PubMed  CAS  Google Scholar 

  51. Li Z, Colucci-Guyon E, Pincon-Raymond M, Mericskay M, Pournin S, Paulin D, Babinet C (1996) Cardiovascular lesions and skeletal myopathy in mice lacking desmin. Dev Biol 175:362–366

    Article  PubMed  CAS  Google Scholar 

  52. Capetanaki Y, Milner DJ, Weitzer G (1997) Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct Funct 22:103–116

    Article  PubMed  CAS  Google Scholar 

  53. Milner DJ, Taffet GE, Wang X, Pham T, Tamura T, Hartley C, Gerdes AM, Capetanaki Y (1999) The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function. J Mol Cell Cardiol 31:2063–2076

    Article  PubMed  CAS  Google Scholar 

  54. Haubold KW, Allen DL, Capetanaki Y, Leinwand LA (2003) Loss of desmin leads to impaired voluntary wheel running and treadmill exercise performance. J Appl Physiol 95:1617–1622

    PubMed  CAS  Google Scholar 

  55. Balogh J, Merisckay M, Li Z, Paulin D, Arner A (2002) Hearts from mice lacking desmin have a myopathy with impaired active force generation and unaltered wall compliance. Cardiovasc Res 53:439–450

    Article  PubMed  CAS  Google Scholar 

  56. Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000) Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. J Cell Biol 150:1283–1298

    Article  PubMed  CAS  Google Scholar 

  57. Linden M, Li Z, Paulin D, Gotow T, Leterrier JF (2001) Effects of desmin gene knockout on mice heart mitochondria. J Bioenerg Biomembr 33:333–341

    Article  PubMed  CAS  Google Scholar 

  58. Weisleder N, Taffet GE, Capetanaki Y (2004) Bcl-2 overexpression corrects mitochondrial defects and ameliorates inherited desmin null cardiomyopathy. Proc Natl Acad Sci USA 101:769–774

    Article  PubMed  CAS  Google Scholar 

  59. Wang X, Li F, Campbell SE, Gerdes AM (1999) Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: II. Cytoskeletal remodeling. J Mol Cell Cardiol 31:319–331

    Article  PubMed  CAS  Google Scholar 

  60. Collins JF, Pawloski-Dahm C, Davis MG, Ball N, Dorn GW II, Walsh RA (1996) The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. J Mol Cell Cardiol 28:1435–1443

    Article  PubMed  CAS  Google Scholar 

  61. Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, Devaux B, Bauer E, Klovekorn WP, Schlepper M, Schaper W, Schaper J (2000) Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circ Res 86:846–853

    Article  PubMed  CAS  Google Scholar 

  62. Wang X, Osinska H, Gerdes AM, Robbins J (2002) Desmin filaments and cardiac disease: establishing causality. J Card Fail 8:S287–S292

    Article  PubMed  CAS  Google Scholar 

  63. Chen F, Chang R, Trivedi M, Capetanaki Y, Cryns VL (2003) Caspase proteolysis of desmin produces a dominant-negative inhibitor of intermediate filaments and promotes apoptosis. J Biol Chem 278:6848–6853

    Article  PubMed  CAS  Google Scholar 

  64. Panagopoulou P, Davos CH, Milner DJ, Varela E, Cameron J, Mann DL, Capetanaki Y (2008) Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure. J Cell Biol 181:761–775

    Article  PubMed  CAS  Google Scholar 

  65. Bennardini F, Wrzosek A, Chiesi M (1992) Alpha B-crystallin in cardiac tissue. Association with actin and desmin filaments. Circ Res 71:288–294

    Article  PubMed  CAS  Google Scholar 

  66. Hwang DM, Dempsey AA, Wang RX, Rezvani M, Barrans JD, Dai KS, Wang HY, Ma H, Cukerman E, Liu YQ, Gu JR, Zhang JH, Tsui SK, Waye MM, Fung KP, Lee CY, Liew CC (1997) A genome-based resource for molecular cardiovascular medicine: toward a compendium of cardiovascular genes. Circulation 96:4146–4203

    Article  PubMed  CAS  Google Scholar 

  67. Arbustini E, Morbini P, Grasso M, Fasani R, Verga L, Bellini O, Dal Bello B, Campana C, Piccolo G, Febo O, Opasich C, Gavazzi A, Ferrans VJ (1998) Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits. J Am Coll Cardiol 31:645–653

    Article  PubMed  CAS  Google Scholar 

  68. Maloyan A, Osinska H, Lammerding J, Lee RT, Cingolani OH, Kass DA, Lorenz JN, Robbins J (2009) Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy. Circ Res 104:1021–1028

    Article  PubMed  CAS  Google Scholar 

  69. Maloyan A, Sanbe A, Osinska H, Westfall M, Robinson D, Imahashi K, Murphy E, Robbins J (2005) Mitochondrial dysfunction and apoptosis underlie the pathogenic process in alpha-B-crystallin desmin-related cardiomyopathy. Circulation 112:3451–3461

    Article  PubMed  CAS  Google Scholar 

  70. Maloyan A, Sayegh J, Osinska H, Chua BH, Robbins J (2010) Manipulation of death pathways in desmin-related cardiomyopathy. Circ Res 106:1524–1532

    Article  PubMed  CAS  Google Scholar 

  71. Sanbe A, Osinska H, Villa C, Gulick J, Klevitsky R, Glabe CG, Kayed R, Robbins J (2005) Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. Proc Natl Acad Sci USA 102:13592–13597

    Article  PubMed  CAS  Google Scholar 

  72. Sanbe A, Yamauchi J, Miyamoto Y, Fujiwara Y, Murabe M, Tanoue A (2007) Interruption of CryAB-amyloid oligomer formation by HSP22. J Biol Chem 282:555–563

    Article  PubMed  CAS  Google Scholar 

  73. Glabe CG, Kayed R (2006) Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology 66:74–78

    Article  Google Scholar 

  74. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489

    Article  PubMed  CAS  Google Scholar 

  75. Tannous P, Zhu H, Johnstone JL, Shelton JM, Rajasekaran NS, Benjamin IJ, Nguyen L, Gerard RD, Levine B, Rothermel BA, Hill JA (2008) Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc Natl Acad Sci USA 105:9745–9750

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The research in the authors’ laboratory is supported by National Institutes of health (NIH) grants P01HL69799, P50HL074728, P50HL077101, P01HL059408, and R01HL087862 (to J.R.). National Institutes of Health fellowship awards T32 HL07752 and F32 HL087478; and an American Heart Association Postdoctoral Fellowship (to JSP).

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  1. Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, MLC 7020, 45229–3039, Cincinnati, OH, USA

    J. Scott Pattison & Jeffrey Robbins

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Correspondence to Jeffrey Robbins .

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  1. Australia for Medical Research, Iron Metabolism Program, Children's Cancer Institute, Randwick, New South Wales, Australia

    Maria Kavallaris

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Pattison, J.S., Robbins, J. (2012). Desmin and Heart Disease. In: Kavallaris, M. (eds) Cytoskeleton and Human Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-788-0_19

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