Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1

Abstract

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.

Differentiation defects in primary motoneurons from a SMARD1 mouse model that are insensitive to treatment with low dose PEGylated IGF1

“…As it is currently known, PEG-IGF1 stimulates the Akt/protein S6 kinase phosphorylation in isolated motoneurons and in spinal cord tissue from Nmd 2J mice, but does not prevent motoneuron degeneration in vivo 11 and differentiation defects in vitro (Fig. 2E).…”

“…This is in contrast to the observed positive effects in striated muscles of Nmd 2J mice. Four-week treatment with 0.05 mg/kg PEG-IGF1 delayed muscle fiber degeneration, both in the gastrocnemius muscle and the diaphragm 11 . One reason might be the “underdosed” treatment, as already discussed by Krieger et al 11 as doses higher than 0.05 mg/kg were not tolerated by the Nmd 2J mouse.…”

“…These observations raised the question whether and which cell autonomous disease mechanisms in motoneurons cause dysfunction and loss in consequence of Ighmbp2 deficiency. We could previously show that a systemic application of a polyethylene glycol-coupled IGF1 (PEG-IGF1) 10 resulted in enhanced muscle strength accompanied by a significant improvement of muscle fiber calibers in Nmd 2J mice 11 . In addition, PEG-IGF1 supported axonal sprouting at the nerve terminals of the gastrocnemius muscle leading to reduced denervation activity 11 .…”

“…We could previously show that a systemic application of a polyethylene glycol-coupled IGF1 (PEG-IGF1) 10 resulted in enhanced muscle strength accompanied by a significant improvement of muscle fiber calibers in Nmd 2J mice 11 . In addition, PEG-IGF1 supported axonal sprouting at the nerve terminals of the gastrocnemius muscle leading to reduced denervation activity 11 . Although PEG-IGF1 stimulated the phosphorylation of the ribosomal protein S6 kinase in spinal cord of Nmd 2J mice, 11 the treatment did not increase motoneuron survival as recently reported for the progressive motoneuronopathy ( pmn ) mouse model 12 .…”

“…In addition, PEG-IGF1 supported axonal sprouting at the nerve terminals of the gastrocnemius muscle leading to reduced denervation activity 11 . Although PEG-IGF1 stimulated the phosphorylation of the ribosomal protein S6 kinase in spinal cord of Nmd 2J mice, 11 the treatment did not increase motoneuron survival as recently reported for the progressive motoneuronopathy ( pmn ) mouse model 12 . These observations led to the hypothesis that Ighmbp2-deficient motoneurons may not be amenable to PEG-IGF1, and survival is a cell autonomous disease mechanism caused by Ighmbp2 deficiency, which can’t be compensated by enhanced protein S6 kinase signaling.…”