The Heart-Brain Connection in Patients with Duchenne Muscular Dystrophy

  • Claudia Bearzi
  • Roberto RizziEmail author
Reference work entry


Duchenne muscular dystrophy (DMD) is a progressive form of muscular dystrophy that occurs primarily in males and though in rare cases may affect females. It is caused by mutations in the DMD gene, which result in the completely lack of the related protein dystrophin (Dp427). Absence of Dp427 causes progressive weakening and degeneration of muscles. In addition, beyond skeletal muscle, these mutations alter the respiratory and heart performances, representing the leading causes of death in these patients. Furthermore, certain neuronal populations express Dp427, whose perturbation is correlated with several neural disorders in DMD patients. Recently, it has been hypothesized that dystrophin could play a fundamental role also in the axonal growth mediated by the nerve growth factor (NGF). Indeed, different studies have shown that in a dystrophic scenario, different neural populations exhibit reduced responsiveness to NGF stimulation, compared to controls. Parameters, such as number and length of neurites, growth cone advancement, and receptor ligand responsiveness (NGF/TrkA), are significantly reduced in neurons deriving from DMD patients or dystrophin-deficient (mdx) mice, a murine dystrophic model. Remarkably, the reduced sympathetic innervation affects even more distal districts, such as the heart, disturbing electrophysiology, beating, and contraction force. A deepen analysis of the relationship between the heart and brain in the context of DMD offers a new strategy for patient stratification and knowledge of the pathology that could open up new therapeutic scenarios.


Heart Brain Innervation Duchenne muscular dystrophy Nerve growth factor Sympathetic nervous system Fibrosis Postganglionic adrenergic neurons 


  1. 1.
    Bennet MR, Gibson WG, Lemon G. Neuronal cell death, nerve growth factor and neurotrophic models: 50 years on. Auton Neurosci. 2002;95(1–2):1–23.PubMedGoogle Scholar
  2. 2.
    Blake DJ, Tinsley JM, Davies KE. Utrophin: a structural and functional comparison to dystrophin. Brain Pathol. 1996;6(1):37–47.PubMedGoogle Scholar
  3. 3.
    Blake DJ, Weir A, Newey SE, Davies KE. Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol Rev. 2002;82(2):291–329. Scholar
  4. 4.
    Boveda S, Galinier M, Pathak A, Fourcade J, Dongay B, Benchendikh D, et al. Prognostic value of heart rate variability in time domain analysis in congestive heart failure. J Interv Card Electrophysiol. 2001;5(2):181–7.PubMedGoogle Scholar
  5. 5.
    Bulfield G, Siller WG, Wight PA, Moore KJ. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A. 1984;81(4):1189–92.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Cao DJ, Wang ZV, Battiprolu PK, Jiang N, Morales CR, Kong Y, et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy. Proc Natl Acad Sci U S A. 2011;108(10):4123–8. Scholar
  7. 7.
    Carretta D, Santarelli M, Vanni D, Carrai R, Sbriccoli A, Pinto F, et al. The organisation of spinal projecting brainstem neurons in an animal model of muscular dystrophy. A retrograde tracing study on mdx mutant mice. Brain Res. 2001;895(1–2):213–22.PubMedGoogle Scholar
  8. 8.
    Choate JK, Klemm M, Hirst GD. Sympathetic and parasympathetic neuromuscular junctions in the guinea-pig sino-atrial node. J Auton Nerv Syst. 1993;44(1):1–15.PubMedGoogle Scholar
  9. 9.
    Chu V, Otero JM, Lopez O, Sullivan MF, Morgan JP, Amende I, et al. Electrocardiographic findings in mdx mice: a cardiac phenotype of Duchenne muscular dystrophy. Muscle Nerve. 2002;26(4):513–9. Scholar
  10. 10.
    Consalvi S, Saccone V, Mozzetta C. Histone deacetylase inhibitors: a potential epigenetic treatment for Duchenne muscular dystrophy. Epigenomics. 2014;6(5):547–60. Scholar
  11. 11.
    Cox GF, Kunkel LM. Dystrophies and heart disease. Curr Opin Cardiol. 1997;12(3):329–43.PubMedGoogle Scholar
  12. 12.
    D’Orsogna L, O’Shea JP, Miller G. Cardiomyopathy of Duchenne muscular dystrophy. Pediatr Cardiol. 1988;9(4):205–13. Scholar
  13. 13.
    De Stefano ME, Leone L, Lombardi L, Paggi P. Lack of dystrophin leads to the selective loss of superior cervical ganglion neurons projecting to muscular targets in genetically dystrophic mdx mice. Neurobiol Dis. 2005;20(3):929–42. Scholar
  14. 14.
    Del Signore A, Gotti C, De Stefano ME, Moretti M, Paggi P. Dystrophin stabilizes alpha 3- but not alpha 7-containing nicotinic acetylcholine receptor subtypes at the postsynaptic apparatus in the mouse superior cervical ganglion. Neurobiol Dis. 2002;10(1):54–66.PubMedGoogle Scholar
  15. 15.
    Deppmann CD, Mihalas S, Sharma N, Lonze BE, Niebur E, Ginty DD. A model for neuronal competition during development. Science. 2008;320(5874):369–73. Scholar
  16. 16.
    Dittrich S, Tuerk M, Haaker G, Greim V, Buchholz A, Burkhardt B, et al. Cardiomyopathy in Duchenne muscular dystrophy: current value of clinical, electrophysiological and imaging findings in children and teenagers. Klin Padiatr. 2015;227(4):225–31. Scholar
  17. 17.
    Dovey OM, Foster CT, Conte N, Edwards SA, Edwards JM, Singh R, et al. Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice. Blood. 2013;121(8):1335–44. Scholar
  18. 18.
    Duchenne and Becker muscular dystrophy. Genetics Home Reference (GHAR). 2016.Google Scholar
  19. 19.
    Gilbert R, Nalbantoglu J, Petrof BJ, Ebihara S, Guibinga GH, Tinsley JM, et al. Adenovirus-mediated utrophin gene transfer mitigates the dystrophic phenotype of mdx mouse muscles. Hum Gene Ther. 1999;10(8):1299–310. Scholar
  20. 20.
    Glebova NO, Ginty DD. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J Neurosci. 2004;24(3):743–51. Scholar
  21. 21.
    Glebova NO, Ginty DD. Growth and survival signals controlling sympathetic nervous system development. Annu Rev Neurosci. 2005;28:191–222. Scholar
  22. 22.
    Gold BG, Spencer P. Neurotrophic function in normal nerve and in peripheral neuropathies. New York: Raven Press; 1993.Google Scholar
  23. 23.
    Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol. 2015;7(4):204–14. Scholar
  24. 24.
    Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS, Sanes JR. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell. 1997;90(4):729–38.PubMedGoogle Scholar
  25. 25.
    Hasan W, Jama A, Donohue T, Wernli G, Onyszchuk G, Al-Hafez B, et al. Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats. Brain Res. 2006;1124(1):142–54. Scholar
  26. 26.
    Heerssen HM, Pazyra MF, Segal RA. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci. 2004;7(6):596–604. Scholar
  27. 27.
    Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 2003;72:609–42. Scholar
  28. 28.
    Ieda M, Fukuda K, Hisaka Y, Kimura K, Kawaguchi H, Fujita J, et al. Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression. J Clin Invest. 2004;113(6):876–84. Scholar
  29. 29.
    Ieda M, Kanazawa H, Kimura K, Hattori F, Ieda Y, Taniguchi M, et al. Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nat Med. 2007;13(5):604–12. Scholar
  30. 30.
    Iwata Y, Katanosaka Y, Arai Y, Komamura K, Miyatake K, Shigekawa M. A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel. J Cell Biol. 2003;161(5):957–67. Scholar
  31. 31.
    Judge DP, Kass DA, Thompson WR, Wagner KR. Pathophysiology and therapy of cardiac dysfunction in Duchenne muscular dystrophy. Am J Cardiovasc Drugs. 2011;11(5):287–94. Scholar
  32. 32.
    Jung C, Chylinski TM, Pimenta A, Ortiz D, Shea TB. Neurofilament transport is dependent on actin and myosin. J Neurosci. 2004;24(43):9486–96. Scholar
  33. 33.
    Kamdar F, Garry DJ. Dystrophin-deficient cardiomyopathy. J Am Coll Cardiol. 2016;67(21):2533–46. Scholar
  34. 34.
    Kanazawa H, Fukuda K. Cardiac sympathetic nerve plasticity and heart failure. J Pain Relief. 2016;5:1. Scholar
  35. 35.
    Kaspar RW, Allen HD, Montanaro F. Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy. J Am Acad Nurse Pract. 2009;21(5):241–9. Scholar
  36. 36.
    Khairallah M, Khairallah R, Young ME, Dyck JR, Petrof BJ, Des Rosiers C. Metabolic and signaling alterations in dystrophin-deficient hearts precede overt cardiomyopathy. J Mol Cell Cardiol. 2007;43(2):119–29. Scholar
  37. 37.
    Korsching S, Thoenen H. Developmental changes of nerve growth factor levels in sympathetic ganglia and their target organs. Dev Biol. 1988;126(1):40–6.PubMedGoogle Scholar
  38. 38.
    Lanza GA, Guido V, Galeazzi MM, Mustilli M, Natali R, Ierardi C, et al. Prognostic role of heart rate variability in patients with a recent acute myocardial infarction. Am J Cardiol. 1998;82(11):1323–8.PubMedGoogle Scholar
  39. 39.
    Larsen HE, Lefkimmiatis K, Paterson DJ. Sympathetic neurons are a powerful driver of myocyte function in cardiovascular disease. Sci Rep. 2016;6:38898. Scholar
  40. 40.
    Licursi V, Caiello I, Lombardi L, De Stefano ME, Negri R, Paggi P. Lack of dystrophin in mdx mice modulates the expression of genes involved in neuron survival and differentiation. Eur J Neurosci. 2012;35(5):691–701. Scholar
  41. 41.
    Lockhart ST, Turrigiano GG, Birren SJ. Nerve growth factor modulates synaptic transmission between sympathetic neurons and cardiac myocytes. J Neurosci. 1997;17(24):9573–82.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Lombardi L, De Stefano ME, Paggi P. Components of the NGF signaling complex are altered in mdx mouse superior cervical ganglion and its target organs. Neurobiol Dis. 2008;32(3):402–11. Scholar
  43. 43.
    Lombardi L, Persiconi I, Gallo A, Hoogenraad CC, De Stefano ME. NGF-dependent axon growth and regeneration are altered in sympathetic neurons of dystrophic mdx mice. Mol Cell Neurosci. 2017;80:1–17. Scholar
  44. 44.
    Love DR, Hill DF, Dickson G, Spurr NK, Byth BC, Marsden RF, et al. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature. 1989;339(6219):55–8. Scholar
  45. 45.
    Marques MJ, Oggiam DS, Barbin IC, Ferretti R, Santo Neto H. Long-term therapy with deflazacort decreases myocardial fibrosis in mdx mice. Muscle Nerve. 2009;40(3):466–8. Scholar
  46. 46.
    McKinsey TA. Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol Toxicol. 2012;52:303–19. Scholar
  47. 47.
    Mehler MF. Brain dystrophin, neurogenetics and mental retardation. Brain Res Brain Res Rev. 2000;32(1):277–307.PubMedGoogle Scholar
  48. 48.
    Michele DE, Campbell KP. Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem. 2003;278(18):15457–60. Scholar
  49. 49.
    Milan M, Pace V, Maiullari F, Chirivi M, Baci D, Maiullari S, et al. Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation. Cell Death Dis. 2018;9(2):108. Scholar
  50. 50.
    Miller G, D’Orsogna L, O’Shea JP. Autonomic function and the sinus tachycardia of Duchenne muscular dystrophy. Brain and Development. 1989;11(4):247–50.PubMedGoogle Scholar
  51. 51.
    Mok SA, Lund K, Campenot RB. A retrograde apoptotic signal originating in NGF-deprived distal axons of rat sympathetic neurons in compartmented cultures. Cell Res. 2009;19(5):546–60. Scholar
  52. 52.
    Oppenheim RW. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci. 1989;12(7):252–5.PubMedGoogle Scholar
  53. 53.
    Pagani M, Malfatto G, Pierini S, Casati R, Masu AM, Poli M, et al. Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy. J Auton Nerv Syst. 1988;23(2):143–53.PubMedGoogle Scholar
  54. 54.
    Perloff JK. Cardiac rhythm and conduction in Duchenne’s muscular dystrophy: a prospective study of 20 patients. J Am Coll Cardiol. 1984;3(5):1263–8.PubMedGoogle Scholar
  55. 55.
    Pilgram GS, Potikanond S, Baines RA, Fradkin LG, Noordermeer JN. The roles of the dystrophin-associated glycoprotein complex at the synapse. Mol Neurobiol. 2010;41(1):1–21. Scholar
  56. 56.
    Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016;119(1):91–112. Scholar
  57. 57.
    Quinlan JG, Hahn HS, Wong BL, Lorenz JN, Wenisch AS, Levin LS. Evolution of the mdx mouse cardiomyopathy: physiological and morphological findings. Neuromuscul Disord. 2004;14(8–9):491–6. Scholar
  58. 58.
    Ryan TD, Taylor MD, Mazur W, Cripe LH, Pratt J, King EC, et al. Abnormal circumferential strain is present in young Duchenne muscular dystrophy patients. Pediatr Cardiol. 2013;34(5):1159–65. Scholar
  59. 59.
    Sapp JL, Bobet J, Howlett SE. Contractile properties of myocardium are altered in dystrophin-deficient mdx mice. J Neurol Sci. 1996;142(1–2):17–24.PubMedGoogle Scholar
  60. 60.
    Schinder AF, Poo M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 2000;23(12):639–45.PubMedGoogle Scholar
  61. 61.
    Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J, Lehnart SE, et al. Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest. 2010;120(12):4388–98. Scholar
  62. 62.
    Shcherbakova OG, Hurt CM, Xiang Y, Dell’Acqua ML, Zhang Q, Tsien RW, et al. Organization of beta-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes. J Cell Biol. 2007;176(4):521–33. Scholar
  63. 63.
    Shein NA, Shohami E. Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries. Mol Med. 2011;17(5–6):448–56. Scholar
  64. 64.
    Shimizu-Motohashi Y, Komaki H, Motohashi N, Takeda S, Yokota T, Aoki Y. Restoring dystrophin expression in Duchenne muscular dystrophy: current status of therapeutic approaches. J Pers Med. 2019;9(1).
  65. 65.
    Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 2000;48(2):218–26. Scholar
  66. 66.
    Tan J, Cang S, Ma Y, Petrillo RL, Liu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hematol Oncol. 2010;3:5. Scholar
  67. 67.
    Thomas TO, Morgan TM, Burnette WB, Markham LW. Correlation of heart rate and cardiac dysfunction in Duchenne muscular dystrophy. Pediatr Cardiol. 2012;33(7):1175–9. Scholar
  68. 68.
    Tyler KL. Origins and early descriptions of “Duchenne muscular dystrophy”. Muscle Nerve. 2003;28(4):402–22. Scholar
  69. 69.
    Vaillend C, Billard JM, Laroche S. Impaired long-term spatial and recognition memory and enhanced CA1 hippocampal LTP in the dystrophin-deficient Dmd(mdx) mouse. Neurobiol Dis. 2004;17(1):10–20. Scholar
  70. 70.
    Wang X, Liu J, Zhen J, Zhang C, Wan Q, Liu G, et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int. 2014;86(4):712–25. Scholar
  71. 71.
    Wingerd KL, Goodman NL, Tresser JW, Smail MM, Leu ST, Rohan SJ, et al. Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart. J Neurosci. 2002;22(24):10772–80.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Yang JY, Wang Q, Wang W, Zeng LF. Histone deacetylases and cardiovascular cell lineage commitment. World J Stem Cells. 2015;7(5):852–8. Scholar
  73. 73.
    Yoo WH, Cho MJ, Chun P, Kim KH, Lee JS, Shin YB. The evolution of electrocardiographic changes in patients with Duchenne muscular dystrophies. Korean J Pediatr. 2017;60(6):196–201. Scholar
  74. 74.
    Yotsukura M, Sasaki K, Kachi E, Sasaki A, Ishihara T, Ishikawa K. Circadian rhythm and variability of heart rate in Duchenne-type progressive muscular dystrophy. Am J Cardiol. 1995;76(12):947–51.PubMedGoogle Scholar
  75. 75.
    Yotsukura M, Fujii K, Katayama A, Tomono Y, Ando H, Sakata K, et al. Nine-year followup study of heart rate variability in patients with Duchenne-type progressive muscular dystrophy. Am Heart J. 1998;136(2):289–96. Scholar
  76. 76.
    Yucel N, Chang AC, Day JW, Rosenthal N, Blau HM. Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ Regen Med. 2018;3:4.
  77. 77.
    Zaglia T, Mongillo M. Cardiac sympathetic innervation, from a different point of (re)view. J Physiol. 2017;595(12):3919–30. Scholar
  78. 78.
    Zaglia T, Milan G, Franzoso M, Bertaggia E, Pianca N, Piasentini E, et al. Cardiac sympathetic neurons provide trophic signal to the heart via beta2-adrenoceptor-dependent regulation of proteolysis. Cardiovasc Res. 2013;97(2):240–50. Scholar
  79. 79.
    Zaika O, Zhang J, Shapiro MS. Functional role of M-type (KCNQ) K(+) channels in adrenergic control of cardiomyocyte contraction rate by sympathetic neurons. J Physiol. 2011;589(Pt 10):2559–68.

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Institute for Genetic and Biomedical Research (IRGB), National Research Council of Italy (CNR)MilanItaly
  2. 2.Fondazione Giovanni Paolo IICampobassoItaly
  3. 3.Institute of Cell Biology and Neurobiology (IBCN), National Research Council of Italy (CNR)RomeItaly
  4. 4.Fondazione Istituto Nazionale di Genetica Molecolare (INGM) “Romeo ed Enrica Invernizzi”MilanItaly

Section editors and affiliations

  • Alessia Pascale
    • 1
  • Emilia d'Elia
    • 2
  1. 1.Department of Drug Sciences, Section of PharmacologyUniversity of PaviaPaviaItaly
  2. 2.Dipartimento CardiovascolareAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly

Personalised recommendations