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.

Key points summary

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.

This study mapped the trajectory of muscle ageing at the whole-body, whole-muscle, and cellular level in 96 healthy females aged between 18 and 80 years old, while controlling fo confounding lifestyle factors. Muscle mass and function declined with age, concomitant to a reduction in type I fibre size and increase in hybrid type I/IIa fibres. Patterns of muscle gene expression wer mapped across ageing, showing an increase in immune cell signalling and a decline in mitochondrial respiration pathways. Circulating sex hormones were significantly associated with muscle mass morphology, and gene expression across the lifespan.

The authors have declared no competing interest.

This study was funded by an Australian Research Council Future Fellowship (FT10100278).

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The Human Research Ethics Committee of Deakin University gave ethical approval for this work (project number 2021-307).

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