HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy

English version České info

Huntington’s disease (HD) is a neurodegenerative disorder in which the mutation results in an extra-long tract of glutamines that causes the huntingtin protein to aggregate. It is characterized by neurological symptoms and brain pathology, which is associated with nuclear and cytoplasmic protein aggregates and with transcriptional deregulation. Despite the fact that HD has been recognized principally as a neurological disease, there are multiple studies indicating that peripheral pathologies including cardiac dysfunction and skeletal muscle atrophy, contribute to the overall progression of HD. To unravel the cause of the skeletal muscle dysfunction, we applied a wide range of molecular and physiological methods to the analysis of two well established genetic mouse models of this disease. We found that symptomatic animals developed muscle dysfunction characterised by a change in the contractile characteristics of fast twitch muscles and a decrease in twitch and tetanic force of hindlimb muscles. In addition, there is a significant decrease in the number of motor units innervating the EDL muscle, and this motor unit loss progresses during the course of the disease. These changes were accompanied by the re-expression of contractile transcripts and markers of muscle denervation such as the HDAC4-Dach2-myogenin axis, as well as the apparent deterioration in energy metabolism and decreased oxidation. Therefore, we conclude, that the HD-related skeletal muscle atrophy is accompanied by progressive loss of functional motor units.

Vyšlo v časopise: HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005021
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005021

Souhrn

Zdroje

1. Bates GP, Tabrizi SJ, Jones AL (2014) Huntington's Disease. New York: Oxford University Press.

2. Strong TV, Tagle DA, Valdes JM, Elmer LW, Boehm K, et al. (1993) Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet 5: 259–265. 8275091

3. Li SH, Schilling G, Young WS 3rd, Li XJ, Margolis RL, et al. (1993) Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11: 985–993. 8240819

4. Li SH, Li XJ (2004) Huntingtin-protein interactions and the pathogenesis of Huntington's disease. Trends Genet 20: 146–154. 15036808

5. Li W, Serpell LC, Carter WJ, Rubinsztein DC, Huntington JA (2006) Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J Biol Chem 281: 15916–15922. 16595690

6. Harjes P, Wanker EE (2003) The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28: 425–433. 12932731

7. Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat Genet 11: 155–163. 7550343

8. Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, et al. (1999) Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J Neurosci 19: 2522–2534. 10087066

9. Sathasivam K, Lane A, Legleiter J, Warley A, Woodman B, et al. (2010) Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington's disease. Hum Mol Genet 19: 65–78. doi: 10.1093/hmg/ddp467 19825844

10. Moffitt H, McPhail GD, Woodman B, Hobbs C, Bates GP (2009) Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington's disease. PLoS One 4: e8025. doi: 10.1371/journal.pone.0008025 19956633

11. Zielonka D, Piotrowska I, Mielcarek M (2014) Cardiac dysfunction in Huntington’s Disease. Exp Clin Cardiol 20: 2547–2554.

12. Pattison JS, Sanbe A, Maloyan A, Osinska H, Klevitsky R, et al. (2008) Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. Circulation 117: 2743–2751. doi: 10.1161/CIRCULATIONAHA.107.750232 18490523

13. Mielcarek M, Inuabasi L, Bondulich MK, Muller T, Osborne GF, et al. (2014) Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease. PLoS Genet 10: e1004550. doi: 10.1371/journal.pgen.1004550 25101683

14. Mielcarek M, Bondulich MK, Inuabasi L, Franklin SA, Muller T, et al. (2014) The Huntington's Disease-Related Cardiomyopathy Prevents a Hypertrophic Response in the R6/2 Mouse Model. PLoS One 9: e108961. doi: 10.1371/journal.pone.0108961 25268775

15. van der Burg JM, Bjorkqvist M, Brundin P (2009) Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol 8: 765–774. doi: 10.1016/S1474-4422(09)70178-4 19608102

16. Zielonka D, Piotrowska I, Marcinkowski JT, Mielcarek M (2014) Skeletal muscle pathology in Huntington's disease. Front Physiol 5:380: 1–5.

17. Kosinski CM, Schlangen C, Gellerich FN, Gizatullina Z, Deschauer M, et al. (2007) Myopathy as a first symptom of Huntington's disease in a Marathon runner. Mov Disord 22: 1637–1640. 17534945

18. Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, et al. (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11: 1911–1926. 12165554

19. Strand AD, Aragaki AK, Shaw D, Bird T, Holton J, et al. (2005) Gene expression in Huntington's disease skeletal muscle: a potential biomarker. Hum Mol Genet 14: 1863–1876. 15888475

20. Lodi R, Schapira AH, Manners D, Styles P, Wood NW, et al. (2000) Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy. Ann Neurol 48: 72–76. 10894218

21. Saft C, Zange J, Andrich J, Muller K, Lindenberg K, et al. (2005) Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease. Mov Disord 20: 674–679. 15704211

22. Ciammola A, Sassone J, Sciacco M, Mencacci NE, Ripolone M, et al. (2011) Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington's disease. Mov Disord 26: 130–137. doi: 10.1002/mds.23258 20931633

23. Quintanilla RA, Johnson GV (2009) Role of mitochondrial dysfunction in the pathogenesis of Huntington's disease. Brain Res Bull 80: 242–247. doi: 10.1016/j.brainresbull.2009.07.010 19622387

24. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1: 361–370. 16054085

25. Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, et al. (2012) Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Hum Mol Genet 21: 1124–1137. doi: 10.1093/hmg/ddr541 22095692

26. Fujimoto M, Takaki E, Hayashi T, Kitaura Y, Tanaka Y, et al. (2005) Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J Biol Chem 280: 34908–34916. 16051598

27. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, et al. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87: 493–506. 8898202

28. Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, et al. (2001) Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet 10: 137–144. 11152661

29. Woodman B, Butler R, Landles C, Lupton MK, Tse J, et al. (2007) The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res Bull 72: 83–97. 17352931

30. Sathasivam K, Neueder A, Gipson TA, Landles C, Benjamin AC, et al. (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A 110: 2366–2370. doi: 10.1073/pnas.1221891110 23341618

31. Sathasivam K, Hobbs C, Turmaine M, Mangiarini L, Mahal A, et al. (1999) Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 8: 813–822. 10196370

32. Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, et al. (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 125: 273–288. doi: 10.1007/s00401-012-1043-z 22961620

33. Tsika RW, Schramm C, Simmer G, Fitzsimons DP, Moss RL, et al. (2008) Overexpression of TEAD-1 in transgenic mouse striated muscles produces a slower skeletal muscle contractile phenotype. J Biol Chem 283: 36154–36167. doi: 10.1074/jbc.M807461200 18978355

34. Yoshida T (2008) MCAT elements and the TEF-1 family of transcription factors in muscle development and disease. Arterioscler Thromb Vasc Biol 28: 8–17. 17962623

35. Karasseva N, Tsika G, Ji J, Zhang A, Mao X, et al. (2003) Transcription enhancer factor 1 binds multiple muscle MEF2 and A/T-rich elements during fast-to-slow skeletal muscle fiber type transitions. Mol Cell Biol 23: 5143–5164. 12861002

36. Zhao P, Caretti G, Mitchell S, McKeehan WL, Boskey AL, et al. (2006) Fgfr4 is required for effective muscle regeneration in vivo. Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway. J Biol Chem 281: 429–438. 16267055

37. Mielcarek M, Gunther S, Kruger M, Braun T (2002) VITO-1, a novel vestigial related protein is predominantly expressed in the skeletal muscle lineage. Mech Dev 119 Suppl 1: S269–274. 14516696

38. Mielcarek M, Piotrowska I, Schneider A, Gunther S, Braun T (2009) VITO-2, a new SID domain protein, is expressed in the myogenic lineage during early mouse embryonic development. Gene Expr Patterns 9: 129–137. doi: 10.1016/j.gep.2008.12.002 19118645

39. Gunther S, Mielcarek M, Kruger M, Braun T (2004) VITO-1 is an essential cofactor of TEF1-dependent muscle-specific gene regulation. Nucleic Acids Res 32: 791–802. 14762206

40. Ehrnhoefer DE, Skotte NH, Ladha S, Nguyen YT, Qiu X, et al. (2014) p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. Hum Mol Genet 23: 717–729. doi: 10.1093/hmg/ddt458 24070868

41. Cohen TJ, Barrientos T, Hartman ZC, Garvey SM, Cox GA, et al. (2009) The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity. FASEB J 23: 99–106. doi: 10.1096/fj.08-115931 18780762

42. Cohen TJ, Waddell DS, Barrientos T, Lu Z, Feng G, et al. (2007) The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. J Biol Chem 282: 33752–33759. 17873280

43. Winbanks CE, Beyer C, Hagg A, Qian H, Sepulveda PV, et al. (2013) miR-206 represses hypertrophy of myogenic cells but not muscle fibers via inhibition of HDAC4. PLoS One 8: e73589. doi: 10.1371/journal.pone.0073589 24023888

44. Liu N, Williams AH, Maxeiner JM, Bezprozvannaya S, Shelton JM, et al. (2012) microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. J Clin Invest 122: 2054–2065. doi: 10.1172/JCI62656 22546853

45. Williams AH, Valdez G, Moresi V, Qi X, McAnally J, et al. (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326: 1549–1554. doi: 10.1126/science.1181046 20007902

46. Bruneteau G, Simonet T, Bauche S, Mandjee N, Malfatti E, et al. (2013) Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain 136: 2359–2368. doi: 10.1093/brain/awt164 23824486

47. Bricceno KV, Sampognaro PJ, Van Meerbeke JP, Sumner CJ, Fischbeck KH, et al. (2012) Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice. Hum Mol Genet 21: 4448–4459. 22798624

48. Egerman MA, Glass DJ (2014) Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol 49: 59–68. doi: 10.3109/10409238.2013.857291 24237131

49. Bassel-Duby R, Olson EN (2006) Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem 75: 19–37. 16756483

50. Brooks NE, Myburgh KH (2014) Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways. Front Physiol 5: 99. doi: 10.3389/fphys.2014.00099 24672488

51. Ribchester RR, Thomson D, Wood NI, Hinks T, Gillingwater TH, et al. (2004) Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation. Eur J Neurosci 20: 3092–3114. 15579164

52. Ciciliot S, Rossi AC, Dyar KA, Blaauw B, Schiaffino S (2013) Muscle type and fiber type specificity in muscle wasting. Int J Biochem Cell Biol 45: 2191–2199. doi: 10.1016/j.biocel.2013.05.016 23702032

53. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91: 1447–1531. doi: 10.1152/physrev.00031.2010 22013216

54. Waters CW, Varuzhanyan G, Talmadge RJ, Voss AA (2013) Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction. Proc Natl Acad Sci U S A 110: 9160–9165. doi: 10.1073/pnas.1220068110 23671115

55. Wade A, Jacobs P, Morton AJ (2008) Atrophy and degeneration in sciatic nerve of presymptomatic mice carrying the Huntington's disease mutation. Brain Res 1188: 61–68. 18062944

56. Rozas JL, Gomez-Sanchez L, Tomas-Zapico C, Lucas JJ, Fernandez-Chacon R (2011) Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease. J Neurosci 31: 1106–1113. doi: 10.1523/JNEUROSCI.2011-10.2011 21248135

57. Dogan I, Eickhoff SB, Schulz JB, Shah NJ, Laird AR, et al. (2013) Consistent neurodegeneration and its association with clinical progression in Huntington's disease: a coordinate-based meta-analysis. Neurodegener Dis 12: 23–35. doi: 10.1159/000339528 22922585

58. Koopman R, Ly CH, Ryall JG (2014) A metabolic link to skeletal muscle wasting and regeneration. Front Physiol 5: 32. doi: 10.3389/fphys.2014.00032 24567722

59. Ciammola A, Sassone J, Alberti L, Meola G, Mancinelli E, et al. (2006) Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects. Cell Death Differ 13: 2068–2078. 16729030

60. Ismailoglu I, Chen Q, Popowski M, Yang L, Gross SS, et al. (2014) Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol 391: 230–240. doi: 10.1016/j.ydbio.2014.04.005 24780625

61. Schips TG, Wietelmann A, Hohn K, Schimanski S, Walther P, et al. (2011) FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res 91: 587–597. doi: 10.1093/cvr/cvr144 21628326

62. Hockly E, Woodman B, Mahal A, Lewis CM, Bates G (2003) Standardization and statistical approaches to therapeutic trials in the R6/2 mouse. Brain Res Bull 61: 469–479. 13679245

63. Mielcarek M, Benn CL, Franklin SA, Smith DL, Woodman B, et al. (2011) SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington's disease. PLoS One 6: e27746. doi: 10.1371/journal.pone.0027746 22140466

64. Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, et al. (2013) HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol 11: e1001717. doi: 10.1371/journal.pbio.1001717 24302884

65. Mielcarek M, Seredenina T, Stokes MP, Osborne GF, Landles C, et al. (2013) HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo. PLoS One 8: e80849. doi: 10.1371/journal.pone.0080849 24278330

66. Smolenski RT, Lachno DR, Ledingham SJ, Yacoub MH (1990) Determination of sixteen nucleotides, nucleosides and bases using high-performance liquid chromatography and its application to the study of purine metabolism in hearts for transplantation. J Chromatogr 527: 414–420. 2387888

67. Soppa GK, Smolenski RT, Latif N, Yuen AH, Malik A, et al. (2005) Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle. Am J Physiol Heart Circ Physiol 288: H1468–H1476. 15528231

68. Acevedo-Arozena A, Kalmar B, Essa S, Ricketts T, Joyce P, et al. (2011) A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Dis Model Mech 4: 686–700. doi: 10.1242/dmm.007237 21540242

69. Lu CH, Petzold A, Kalmar B, Dick J, Malaspina A, et al. (2012) Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS. PLoS One 7: e40998. doi: 10.1371/journal.pone.0040998 22815892