Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and
atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd(2J)) mouse shares a crucial mutation in the
immunoglobulin mu-
binding protein 2 gene (Ighmbp2) with
spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as
insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with
polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles.
Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd(2J) mice 2 weeks after birth, which was normalized by
polyethylene glycol-coupled IGF1 treatment. Nmd(2J) mice showed marked neurogenic muscle fibre
atrophy in the gastrocnemius muscle and
polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre
hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of
polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of
polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (
protein kinase B) and the
ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd(2J) mice. Based on these findings,
polyethylene glycol-coupled IGF1 may hold promise as a candidate for future treatment trials in human patients with
spinal muscular atrophy with respiratory distress type 1.