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Abstract
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord
Given that many muscle-centric studies of SMA, using either mouse or cell-culture models, have suggested that myoblast differentiation is affected by Smn deficiency [7, 26,27,28], and suggesting an effect in postnatal muscle growth in vivo, we investigated if aberrant activin/SMAD activity was apparent in the skeletal muscle of 4 week-old C/C muscles
Gene expression of Mstn, Gdf11, and Inhba were all decreased in C/C muscle (Fig 1E), while Cdkn1a showed elevation, consistent with p-SMAD3 elevations
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord. This disorder affects 1 in 11000 infants with a carrier frequency of 1 in 50 [1], resulting from reduced expression of survival motor neuron protein (SMN). Acute type I form is characterized by severe progressive muscle weakness and hypotonia that is seen either at birth or within the first 6 months of life. Children with SMA type I will never be able to sit without support and usually die by the age of two years. Type II and III patients generally have a milder progression and the potential for normal life expectancy
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