Skeletal muscle mitochondrial bioenergetics in humans: Does sex matter?

Skeletal muscle displays remarkable plasticity, and a classical adaptation to exercise training is increased mitochondrial content. Acute exercise induces mitochondrial biogenesis through a complex series of events triggered by disturbances to cellular homeostasis, which activate multiple signalling cascades that converge on the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and lead to a coordinated increase in gene transcription. Mitochondrial content, typically measured using biomarkers such as the maximal activity of citrate synthase, increases over the course of successive exercise sessions owing to a cumulative net positive mitochondrial protein balance, whereby the overall rate of mitochondrial protein synthesis (MitoPS) exceeds breakdown. MitoPS can be measured using stable-isotope tracers, and oral administration of deuterium oxide (D2O) is a valuable tool that allows for integrative measures of protein synthesis to be made over a period of weeks to months in free-living conditions. Sprint interval training (SIT), involving brief, intermittent bursts of ‘all-out’ exercise interspersed with short recovery periods, is a potent stimulus to increase mitochondrial content, similar to traditional endurance training despite reduced exercise volume and time commitment. There is some evidence for sex-based differences in this training response, such that women may experience blunted rates of mitochondrial biogenesis compared with men. Scalzo et al. (2014) assessed MitoPS, based on oral administration of D2O, over 3 weeks of SIT in recreationally active men and women who were matched for baseline fitness. Analysis of skeletal muscle biopsy samples revealed that MitoPS tended to be higher in men compared with women after training. An ontological cluster of 127 mitochondrial proteins was also higher in men compared with women (Scalzo et al., 2014). In our study published in Experimental Physiology (Skelly et al., 2017), we hypothesized that the sex-specific responses suggested by Scalzo et al. (2014) could potentially be explained by a blunted increase in post-exercise mitochondrial gene expression in women compared with men. We measured the mRNA expression of genes involved in mitochondrial biogenesis, including PGC-1α (PPARGC1A), peroxisome proliferator-activated receptor delta (PPARD), PGC-1α-related coactivator (PPRC1) and sirtuin 1 (SIRT1), in response to a single session of SIT in sedentary men and in women who were studied in the follicular phase of their menstrual cycles. Sprint interval training increased the expression of mitochondrial genes after 3 h of recovery compared with pre-exercise, but there were no differences between sexes (Skelly et al., 2017). The findings from our acute study were therefore in contrast to the greater rate of MitoPS observed after training in men compared with women reported by Scalzo et al. (2014). There are several potential explanations for this discrepancy, including the possibility that acute changes in gene expression do not necessarily predict training-induced changes in protein content. Another possibility is that we missed potential sex-based differences in the acute response of mitochondrial gene expression because the single muscle biopsy sampling time point of 3 h post-exercise limited our temporal resolution. It is also possible that women might demonstrate blunted rates of both MitoPS and mitochondrial protein breakdown during short-term SIT, resulting in comparable net changes in mitochondrial content compared with men. Indeed, SIT-induced increases in the protein content of citrate synthase were similar between sexes (Scalzo et al., 2014). Furthermore, it is unknown whether the enhanced MitoPS rates observed in the group of men studied by Scalzo et al. (2014) are present at rest or are primarily related to SIT. Surprisingly, there are a limited number of human sex-based comparisons of basal MitoPS rates in the literature. Cardinale et al. (2018) recognized that despite investigations into the effect of sex on exercise-induced responses (e.g. Scalzo et al., 2014; Skelly et al., 2017), little was known regarding human basal sex-based differences in mitochondrial bioenergetics. Using high-resolution respirometry, the authors demonstrated greater mitochondrial respiration and a lower oxygen affinity, measured as the oxygen tension at 50% of maximal mitochondrial respiration, in isolated mitochondria obtained from women, compared with men who had similar peak aerobic capacity. Maximal mass-specific mitochondrial respiration did not differ between sexes, which is consistent with two other recent reports using permeabilized fibres (Miotto, McGlory, Holloway, Phillips, & Holloway, 2018; Montero, Madsen, Meinild-Lundby, Edin, & Lundby, 2018). The greater intrinsic mitochondrial respiration yet similar mass-specific mitochondrial respiration in women observed by Cardinale et al. (2018) implies that women also had lower mitochondrial content compared with men. However, in the two recent studies, mitochondrial content, assessed using transmission electron microscopy to determine mitochondrial volume (Montero et al., 2018) and Western blotting to determine mitochondrial protein content (Miotto et al., 2018), was higher or similar, respectively, in women compared with men. The conflicting findings might be related to the different methods used to assess content, and highlight an interesting area for continued research. An important consideration in studies of potential sex-based differences is the influence of training status. When closely matched for peak oxygen uptake () relative to kilograms of body mass, women typically have a greater training status owing to a higher proportion of body fat compared with men. Indeed, in the study by Cardinale et al. (2018), the group of women who displayed greater intrinsic mitochondrial respiration compared with men exercised more often (three to four versus two to three sessions per week) and had more experience competing in endurance events, despite having similar (∼50 ml kg−1 min−1). To address the potential influence of training status, the authors also measured mitochondrial function in a group of endurance-trained men with higher (∼67 ml kg−1 min−1) and training history (seven to nine sessions per week). The more well-trained men displayed intrinsic mitochondrial respiration similar to the less well-trained women and higher than the less well-trained men (Cardinale et al., 2018). Together, these findings demonstrate that both training status and sex influence intrinsic mitochondrial respiration. Future research should match men and women for relative to kilograms of fat free mass to account for differences in body composition and training backgrounds. Variability in circulating sex hormones between and within female participants can also influence sex-based comparisons, although this potential confounding factor is often not controlled for in experimental designs. Concentrations of endogenous estradiol and progesterone fluctuate over a naturally occurring menstrual cycle and are suppressed in females using oral contraceptives. It might be worthwhile for researchers examining sex-specific responses to short-term (∼2-wk) exercise interventions to conduct the exercise training within a single menstrual cycle phase (follicular or luteal) in non-oral contraceptive users or within a constant-hormone phase in women using monophasic oral contraceptives. Longer-term exercise interventions could standardize fluctuations in the sex-hormone milieu better by adjusting the length of the intervention to cover a single or multiple complete menstrual cycle(s). Although the effect of menstrual cycle phase on exercise metabolism is likely to be much smaller compared with the effect of sex, these efforts might help to increase the reproducibility of findings and/or limit false conclusions regarding sex-based differences. In summary, the aforementioned studies highlight the potential influence of sex on mitochondrial bioenergetics in humans. Future research should compare exercise-induced changes in mitochondrial respiration and mitochondrial fission and fusion proteins in men and women. Continued investigations into sex-based differences in metabolism at rest and after exercise will expand our understanding of basic human physiology and the regulation of skeletal muscle adaptations. The findings might also provide crucial information for optimizing exercise strategies aimed at improving health in both sexes. We regret our inability to cite all relevant articles owing to space restrictions. None declared.

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