Transcriptomic analysis of aging mouse sciatic nerve reveals early pathways leading to sarcopenia

Background: Sarcopenia, the age-associated decline in skeletal muscle mass and strength, has long been considered a disease of muscle only, but accumulating evidence suggests that sarcopenia could originate from the neural components controlling muscles. To identify early molecular changes in the efferent nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve in aging mice. Methods: Sciatic nerve and gastrocnemius muscle were obtained from young adult, middle-aged, old, and sarcopenic (5,18, 21 and 24 months old, respectively) C57BL/6J female mice (n=6 per age group). Sciatic nerve RNA was extracted and subjected to RNA sequencing (RNA-seq), with real-time quantitative reverse transcription PCR (qRT-PCR) validation of differentially expressed genes (DEGs). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups was performed. Sarcopenia was confirmed with qRT-PCR of previously established markers of sarcopenia onset in gastrocnemius muscle. Results: We detected 33 significant DEGs in sciatic nerve of 18-month-old mice compared to 5-month-old mice (absolute value of fold change > 2; false discovery rate [FDR] < 0.05) which we validated with qRT-PCR of the three top up- and down-regulated genes. Up-regulated genes were associated with circadian rhythm and the AMPK signaling pathway, while down-regulated genes were associated with biosynthesis and metabolic pathways and circadian rhythm. Strikingly, we detected a significant increase in Myog expression (log2 fold change = 18.93, FDR q-value = 1.54x10-12) in sciatic nerve of 18-month-old mice, before up-regulation in muscle was observed. We identified seven clusters of genes with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in sarcopenia initiation including extracellular matrix organization and circadian regulation of gene expression. Conclusions: Gene expression changes in mouse peripheral nerve can be detected prior to overt clinical onset of sarcopenia. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies will validate which of the key changes we reported have disease modifying and/or biomarker potential. ### Competing Interest Statement The authors have declared no competing interest.