Researchers Discover Myogenic Program Dysregulation Contributes to Spinal Muscular Atrophy Disease Pathogenesis
A study entitled “Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy” showed that lack of SMN leads to delayed postnatal skeletal muscle development in mouse models of spinal muscular atrophy. The study was published in the Human Molecular Genetics journal.
Spinal Muscular Atrophy (SMA) is caused by mutations in the Smn1 gene that encodes SMN1 protein, a key protein for motor neuron survival. The lack of SMN protein leads to motor neuron dysfunction and death, triggering subsequent generalized muscle atrophy. However, the contribution of muscle defects to disease pathogenesis remains incompletely understood.
In this study, the authors tackled this issue by performing studies in both in vitro culture of muscle primary cells and in vivo SMA mouse models. To overcome SMN deletion lethality during fetal development of mice, the authors used an intermediate mouse model of SMA developed previously by their team, Smn2B/−, along with other more severe models. The authors detected in primary myoblasts (embryonic cells that will develop into muscle cell or fiber) extracted from Smn2B/− mice reduced levels of muscle regulatory factors and fusion defects. These defects induced a delayed in the muscle program in the skeletal muscle of both Smn2B/− and the more severe SMA models, including (Smn−/−;SMN2 and Smn−/−;SMN2;Δ7). While in the latter there is a dramatic reduction in myogenesis, in the Smn2B/− model, this decrease is observed in an early phase of the disease rescuing at later stages. Thus, SMN reduction leads to abnormal expression of key myogenic genes during development. Performing histological analysis, they found that muscles in these mice were not undergoing degeneration but rather impaired development, denoted by decreased myofiber size and increasing immature myofiber.
The team performed further studies with histone deacetylase (HDAC) inhibitor trichostatin A (TSA), previously shown to extend severe SMA mouse model survival. Their results showed that TSA administration led to improvement of the defects in muscle development.