The Contribution of Oestrogen in Muscle Mass, Function, and Molecular Signalling in Females Aged 18-80

Whether, and how, the menopausal transition mediates the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females between 18-80 years to map the trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade of age, we quantified body composition with dual-energy x-ray absorptiometry, muscle morphology with peripheral quantitative computed tomography, muscle function with leg press and neuromuscular assessment. Vastus lateralis morphology and gene expression was assessed with immunohistochemical staining and RNA sequencing, respectively, and circulating sex hormone concentrations were measured with liquid chromatography mass spectrometry. After adjusting for physical activity and protein intake, age was negatively associated with muscle mass, strength, and overall and type I muscle fibre size, and positively associated with hybrid type I/II fibre prevalence. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion, and extracellular matrix organisation pathways were most up-regulated with age, while mitochondrial function pathways were the most down-regulated. Circulating oestradiol and progesterone, but not testosterone, concentrations across the lifespan were positively associated with lean mass and neuromuscular function, and negatively associated with hybrid muscle fibres. Oestrogen receptor binding sites were significantly enriched in genes that are upregulated in pre- versus post-menopausal muscle, suggesting a reduction in the translation of oestrogen target genes after menopause. The effects of sex hormone fluctuations across the female lifespan should therefore be considered in the development of therapies to combat age-related muscle wasting.