Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy

Gillian K. Maxwell, Eva Szunyogova, Hannah K. Shorrock, Thomas H. Gillingwater, Simon H. Parson

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Abstract

Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre- and early symptomatic ages. However, the left ventricular wall was significantly thinner in SMA mice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagen IV protein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes in SMA hearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology in SMA. In addition, cardiomyocytes in SMA hearts exhibited oxidative stress at pre-symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention in SMA hearts post-fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies for SMA capable of treating non-neuromuscular pathologies.
Original languageEnglish
Pages (from-to)965-978
Number of pages14
JournalJournal of Anatomy
Volume232
Issue number6
Early online date22 Feb 2018
DOIs
Publication statusPublished - Jun 2018

Fingerprint

Spinal Muscular Atrophy
muscular atrophy
pathology
defect
animal models
heart
apoptosis
blood
Pathology
infant mortality
protein
collagen
dilation
fixation
thinning
phenotype
Cardiac Myocytes
Oxidative Stress
oxidative stress
membrane

Keywords

  • cardiac
  • cardiovascular
  • cell death
  • septum
  • stress
  • ventricle

Cite this

Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy. / Maxwell, Gillian K.; Szunyogova, Eva; Shorrock, Hannah K. ; Gillingwater, Thomas H.; Parson, Simon H.

In: Journal of Anatomy, Vol. 232, No. 6, 06.2018, p. 965-978.

Research output: Contribution to journalArticle

Maxwell, Gillian K. ; Szunyogova, Eva ; Shorrock, Hannah K. ; Gillingwater, Thomas H. ; Parson, Simon H. / Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy. In: Journal of Anatomy. 2018 ; Vol. 232, No. 6. pp. 965-978.
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title = "Developmental and Degenerative Cardiac Defects in the Taiwanese Mouse Model of Severe Spinal Muscular Atrophy",
abstract = "Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre- and early symptomatic ages. However, the left ventricular wall was significantly thinner in SMA mice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagen IV protein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes in SMA hearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology in SMA. In addition, cardiomyocytes in SMA hearts exhibited oxidative stress at pre-symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention in SMA hearts post-fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies for SMA capable of treating non-neuromuscular pathologies.",
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note = "We would like to acknowledge the Microscopy and Histology Core Facility at the University of Aberdeen, Kevin Mackenzie, Debbie Wilkinson, Gillian Milne and Lucy Wight, for the use of their facilities. G.K.M. was funded by a research award from RGA awarded to S.H.P. E.S. was funded by a University of Aberdeen Elphinstone PhD Studentship and a research award from the Euan Macdonald Centre for Motor Neurone Disease Research. H.K.S. was funded by a Euan Macdonald Centre for Motor Neurone Disease Research PhD Studentship. S.H.P. is funded by Tenovus (Scotland), SMA Trust and Prinses Beatrix Spierfonds. T.H.G. is funded by SMA Trust (UK SMA Research Consortium Award), Muscular Dystrophy UK, and Anatomical Society (PhD Studentship).",
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AU - Gillingwater, Thomas H.

AU - Parson, Simon H.

N1 - We would like to acknowledge the Microscopy and Histology Core Facility at the University of Aberdeen, Kevin Mackenzie, Debbie Wilkinson, Gillian Milne and Lucy Wight, for the use of their facilities. G.K.M. was funded by a research award from RGA awarded to S.H.P. E.S. was funded by a University of Aberdeen Elphinstone PhD Studentship and a research award from the Euan Macdonald Centre for Motor Neurone Disease Research. H.K.S. was funded by a Euan Macdonald Centre for Motor Neurone Disease Research PhD Studentship. S.H.P. is funded by Tenovus (Scotland), SMA Trust and Prinses Beatrix Spierfonds. T.H.G. is funded by SMA Trust (UK SMA Research Consortium Award), Muscular Dystrophy UK, and Anatomical Society (PhD Studentship).

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N2 - Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre- and early symptomatic ages. However, the left ventricular wall was significantly thinner in SMA mice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagen IV protein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes in SMA hearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology in SMA. In addition, cardiomyocytes in SMA hearts exhibited oxidative stress at pre-symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention in SMA hearts post-fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies for SMA capable of treating non-neuromuscular pathologies.

AB - Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature of SMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre- and early symptomatic ages, in the Taiwanese mouse model of severe SMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre- and early symptomatic ages. However, the left ventricular wall was significantly thinner in SMA mice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagen IV protein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes in SMA hearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology in SMA. In addition, cardiomyocytes in SMA hearts exhibited oxidative stress at pre-symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention in SMA hearts post-fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies for SMA capable of treating non-neuromuscular pathologies.

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KW - cardiovascular

KW - cell death

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