Abstract: Objective To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA). Methods The transgenic mice with type I SMA (Smn-/-SMN20tg/2tg) and littermate control mice (Smn+/-SMN20tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type I SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type I SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice. Results The neonatal mice with type I SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type I SMA mice from 9±1.3 to 11±1.5 days (P<0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type I SMA mice. Type I SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67% ). In primary cultures of hepatocytes from type I SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P<0.01). Conclusion Type I SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.

Key words: spinal muscular atrophy; mice; liver metabolism; molecular pathological mechanism