Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy

Overview

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene, resulting in reduced expression of SMN protein. The disease is characterized by the loss of α-motor neurons, which can lead to skeletal muscle atrophy, reduced bone mineral density, and increased risk of fracture. SMN restoration treatment has been found to improve functional symptoms, although not in full. This study investigates the combined effect of SMN treatment with inhibition of myostatin activation in SMA mice models. Three mice models exhibiting varying severities of SMA were analyzed, including low, low-high, and high-dose SMN restored mice. In order to prevent myostatin activation, mice were treated with muSRK-015P. Mice treated with muSRK-015P exhibited increased gastrocnemius and tibialis anterior (TA) muscle mass. Functional assessment of the plantarflexor muscle group was then conducted using Aurora’s 1300A 3-in-1 Whole Animal System. Although untreated low-high and high dose mice displayed reduced maximal torque, those treated with muSRK-015P showed improvements in maximal torque measurements. To investigate whether the inhibition of myostatin activation could reduce bone deficiencies, mice underwent μCT imaging of the tibias following muSRK-015P treatment. Inhibition of myostatin activation in high dose mice resulted in increased cross-sectional bone area and bone volume. Bone volume and trabecular separation improvements were seen across all mice treated with muSRK-015P. The authors then quantified pre-existing latent myostatin concentrations in WT and SMN-restored mice. Although reduced concentrations were found in low-high dose mice when compared to WT, no differences were observed following normalization to body weight. This suggests that reduced levels of latent myostatin seen in more severe SMA disease models is a result of decreased muscle mass, rather than an upstream cause of which. These data suggest that the inhibition of myostatin activation, especially when combined with SMN restoration, may serve as a beneficial therapeutic treatment for SMA patients.