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Skeletal muscle mitochondrial dysfunction in spinal muscular atrophy

ABSTRACT: The survival motor neuron 1 (SMN1) gene is the causative gene for the spinal muscular atrophy (SMA) disease, the first genetic cause of infant mortality. It affects primarily motor neurons which are the targets of the approved genetic therapies aimed to compensate for the loss of SMN1. However, the limitations of these therapies are now evident since they are not cures, and alternative strategies need to be investigated. Because of the ubiquitous and multifunctional roles of SMN1 in the cell, deeper understanding of the molecular mechanisms underlying intrinsic abnormalities of the different tissues affected by SMA is crucial for the development of new therapeutic approaches. Here we used a muscle specific genetic mouse model for the identification of key cellular processes associated to SMN1 loss, at single myofiber level. We found that mitochondrial dysfunction is a key pathogenetic event in SMA: mitochondria are abnormal with internal degenerated cristae. The ultrastructural changes are coincident with alterations in ROS levels by monoamine oxidase A and Ca2+ homeostasis. Interestingly, the improvements of the myopathic phenotype of the muscle-specific SMA model mice by transplantation of amniotic fluid stem (AFS) cells led to restore mitochondrial function. Our data suggest that a mitochondria-targeting therapy may represent a complementary and broad treatment strategy to further optimize the current treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE207890 | GEO | 2023/03/08

REPOSITORIES: GEO

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