Found in ‘transition’: shifting mechanisms of aerobic exercise adaptation in ageing women

Cardiorespiratory fitness (CRF) declines as a function of human ageing, and likely contributes to the lower exercise capacity and functional independence that is observed in older adults. However, this decline appears to be at least partly reversible through aerobic exercise. Following relatively high-intensity endurance-based training, previously sedentary older men and women both show fairly robust (∼20% or greater) increases in maximal oxygen consumption, suggesting that this adaptive response occurs in older adults of both sexes (Murias et al. 2010). What is notable, though, is that the adaptive mechanisms through which CRF becomes augmented by endurance exercise in older adults appears to be dependent on sex (Spina, 1999; Murias et al. 2010). Unlike their younger female or age-matched male counterparts, older women demonstrate limited adaptations in mechanisms related to convective oxygen (O2) transport, notably: 1) the ability to raise peak cardiac output and systemic O2 delivery or 2) the vasodilator capacity of the skeletal muscle resistance vasculature (Martin et al. 1990; Spina, 1999; Ridout et al. 2005; Murias et al. 2010). Accordingly, improvements in CRF following exercise training in older women seem to be mostly (if not entirely) dependent on peripheral adaptations that enhance the respiratory or diffusion (and thus O2 extraction) capacity of skeletal muscle. While it has been long hypothesized that sex-hormone deficiency may underlie these unique observations in older women (Spina, 1999), what role if any menopause transition-related changes in circulating sex hormones may have on the shifting adaptive responses to exercise training in ageing women has largely been under-investigated. However, a study published in this issue of The Journal of Physiology (Nyberg et al. 2017) provides novel evidence regarding both the time course for and the physiological mechanisms that may underlie this 'shift'. In this study, Nyberg and colleagues from the University of Copenhagen examined leg skeletal muscle biopsies from groups of previously untrained premenopausal and recently (less than 4 years) postmenopausal women before and after 12 weeks of cycling-based endurance training. What is particularly notable is that these two groups of women were relatively well-matched for age (50 vs. 54 years), suggesting that any observed differences in peripheral training adaptations would likely be the result of reproductive age versus chronological age per se. In contrast to their initial hypothesis, the authors observed greater skeletal muscle mitochondrial and microvascular adaptations following endurance training in the legs of postmenopausal compared with premenopausal women. Whereas high-intensity endurance training augmented leg muscle content of several mitochondrial respiratory complexes (specifically complexes II, III and IV) in the early postmenopausal women, these adaptations were not present in the premenopausal group. Similarly, training-induced increases in nitric oxide- and prostaglandin-producing enzymes (i.e. endothelial nitric oxide synthase and cycloxygenase-1) were either augmented or only present, respectively, in the leg muscle of postmenopausal women. These findings (1) reinforce the notion that the menopause transition serves as a critical time period regarding cardiovascular and metabolic function in ageing women, and (2) raise the possibility that the early postmenopausal period creates a skeletal muscle environment that is particularly amenable to exercise-induced increases in oxidative metabolism, or angiogenesis and tissue capillarization. Although it was not specifically measured in the study by Nyberg et al. these leg muscle adaptations could have the potential to elicit an increased peripheral O2 extraction capacity in postmenopausal and older women during maximal exercise. The findings of Nyberg et al. also yield insight into the cellular mechanisms that may underlie these menopause status-dependent responses to exercise training in middle-aged women. Specifically, the authors provide preliminary evidence that the augmented mitochondrial and pro-angiogenic adaptations observed in the postmenopausal group may result from enhanced upregulation of local oestrogen-related receptor α (ERRα) activity. ERRα is a nuclear receptor that appears to act independently of endogenous estrogen, and serve as a key transcriptional activator of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1)-inducible genes, including those of several mitochondrial and microvascular enzymes. Therefore it is notable that 12 weeks of endurance training increased ERRα protein content in the legs of postmenopausal, but not similarly aged premenopausal women. Taken together, an upregulation of exercise-induced ERRα signaling provides a biologically plausible mechanistic pathway for augmented peripheral adaptions in women following menopause. In summary, the recent study by Nyberg et al. (2017) provides some of the first evidence that the sex-dependent adaptations to aerobic exercise training frequently observed in older women may have mechanistic origins in the menopause transition. Specifically, their findings suggest that mitochondrial and microvascular adaptations that could affect the O2 diffusion capacity of skeletal muscle become enhanced from the premenopausal to the early postmenopausal period. These augmented peripheral adaptations may be particularly advantageous for the maintenance and/or preservation of CRF (a major predictor of longevity and functional independence) in older postmenopausal women who traditionally demonstrate a limited ability to improve peak systemic O2 transport through endurance exercise training (Martin et al. 1990; Spina 1999; Murias et al. 2010; Nyberg et al. 2017). Given that the authors did not measure stroke volume or cardiac output responses to maximal exercise in their current study, it remains unknown whether central circulatory adaptations did or did not occur with high-intensity training in the early postmenopausal group (and whether they would have differed from those in the premenopausal women). Therefore, an investigation into whether the early postmenopausal period could represent an 'optimal training window' where peripheral adaptations are augmented prior to adaptations in O2 convection mechanisms becoming limited is clearly warranted. Lastly, a more refined assessment of the time course for 'shifting mechanisms' of aerobic exercise adaptation in ageing women may come from longitudinal training studies using multiple, including perimenopausal, stages of the menopause transition. None declared.