Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.
TL;DR
It is shown that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle.
Abstract
Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.