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 function. 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. 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. 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. Abstract figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/25331955v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@15610c9org.highwire.dtl.DTLVardef@168104corg.highwire.dtl.DTLVardef@105ef53org.highwire.dtl.DTLVardef@a34522_HPS_FORMAT_FIGEXP M_FIG C_FIG 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 for 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 were 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. Key points summary O_LIFemales live longer than males but experience worse disability in the later decades of life, highlighting the need to study female-specific patterns of ageing. C_LIO_LIThis 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. C_LIO_LIUnique 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. C_LIO_LIIndependently 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). C_LIO_LIFluctuations 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. C_LI