Profiling muscle mass, function and molecular signalling in females aged 18–80 years and their associations with sex hormones

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 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 function. Circulating sex hormone concentrations were measured with GC-MS and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. Age was negatively associated with muscle mass, strength and muscle fibre size, and positively associated with hybrid type I/IIa fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion and extracellular matrix organization pathways were the most upregulated with age, whilst 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. Altogether, sex hormone fluctuations across the female lifespan may contribute to age-related muscle wasting, although longitudinal and interventional studies are needed to determine the causal nature of the relationship. KEY POINTS: Females live longer than males but experience worse disability in the later decades of life, highlighting the need to study female-specific patterns of ageing. This study mapped female body composition, muscle morphology, function and gene expression across every decade from 18 to 80 years of age in tightly controlled conditions and examined the relationships with circulating sex hormones. Unique patterns of muscle gene expression across ageing showed an overall increase in immune signalling and a decrease in mitochondrial respiration pathways, but limited associations with circulating sex hormones. Independently of age, circulating oestradiol and progesterone, but not testosterone, were associated with muscle mass and morphology across the lifespan, after adjusting for influential lifestyle factors (protein intake and physical activity). Fluctuations in female sex hormones across the lifespan should be considered when developing therapies to mitigate age-related muscle wasting and improve the female health span.