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.

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

“…Similarly, peripherin-positive neurons were also significantly smaller in SMA mice ( Fig. 5 E), thereby confirming that SMA DRGs were indeed smaller than those in control animals, as has previously been reported for other organs in SMA ( Powis et al , 2016 ; Thomson et al , 2017 ; Maxwell et al , 2018 ). Despite the overall reduced size and disruption to sensory neuron fate in SMA DRGs, these phenotypes were not due to overt cell death in the SMA DRGs ( Supplementary Fig.…”

A mouse model for spinal muscular atrophy provides insights into non-alcoholic fatty liver disease pathogenesis

“…Immune dysregulation has previously been identified in SMA model mice [18][19][20], and we identified a significant reduction in expression of many complement genes ( Fig 2C). Abnormal blood clots have been previously reported in SMA [21,22], and here we found altered transcript levels of genes involved in hemostasis ( Fig 2D).…”

Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance

“…Unresolved RNA:DNA hybrids, induced by SMN depletion, lead to transcriptional termination and consequently cell cycle arrest (Figure 4) [10,11]. It has also been reported that the unresolved R-loop structure due to SMN deficiency in neurons, and oxidative stress in muscles or cardiomyocytes lead to apoptosis [18,24,[38][39][40][41]. Here, we provided additional evidence by showing that a loss of SMN in germ cells also induces programmed cell death in male testis and in developing oocytes in female SMA-like mice (Figures 2 and 4).…”