Menopausal transition alters female skeletal muscle transcriptome

Abstract Objectives Although skeletal muscle is a target of hormonal regulation, the muscle transcriptome, including messenger-RNA (mRNA), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) has not previously been studied across the menopausal transition. Thus, we took a multi-RNA-omics approach to get insight into transcriptome-wide events of menopause. Methods We included baseline and follow-up muscle samples from seven early (EarlyMT) and 17 late perimenopausal (LateMT) women transitioning to early postmenopause during the study. Total RNA was sequenced and differential expression (DE) of the transcriptome was investigated. Gene functions were investigated with pathway analyses and protein level expression with Western Blot. Results We found 30 DE mRNA genes in EarlyMT and 19 in LateMT participating in pathways controlling cell death, growth, and interactions with the external environment. Lack of protein level changes may indicate a specific role of the regulatory RNAs during menopause. 10 DE lncRNA transcripts but no DE lncRNA genes were identified. No DE miRNAs were found. We identified putative regulatory networks likely to be affected by estradiol availability. Changes in gene expression were correlated with changes in body composition variables, indicating that muscularity and adiposity regulators are affected by menopausal transition. We also found correlations between gene expression and physical activity levels. Conclusions The observed DE genes and their regulatory networks offer novel mechanistic insights into factors affecting body composition during and after menopause. Our results imply that physiological deteriorations orchestrated by the muscle transcriptome likely depend on the magnitude of hormonal change and are influenced by physical activity.