Alterations in insulin-like growth factor system in spinal muscular atrophy.

Abstract

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls. A significant decrease in IGF-I levels (mean ± SD: -1.39 ± 1.46 vs. 0.017 ± 0.83, p=.02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4ng/mL vs. 1003.4 ± 274.3ng/mL, p=.03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway. Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.