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

Whether and how ovarian hormone fluctuations mediate 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 of age to map the functional and molecular trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade, we quantified body composition using dual-energy x-ray absorptiometry, muscle morphology using peripheral quantitative computed tomography and voluntary and evoked muscle strength. Circulating sex hormone concentrations were measured with gas chromatography mass spectrometry and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. After adjusting for the relevant variables, age was negatively associated with muscle mass, strength, and muscle fibre size, and positively associated with hybrid type I/II fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion, and extracellular matrix organisation pathways were the most upregulated with age, while mitochondrial function pathways were the most downregulated. Independently of age, circulating oestradiol and progesterone, but not testosterone, concentrations were positively associated with lean mass and negatively associated with hybrid muscle fibres across the lifespan. Oestrogen receptor binding sites were significantly enriched in upregulated genes 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 mitigate age-related muscle wasting.