Unveiling women's powerhouse

Connections link a sequence of three related research papers. The central article which links the other two papers has been published in Experimental Physiology. In a Connections article, an author (or authors) of the central article outlines its principal novel findings, tracing how they were influenced by the first article and how the central article has contributed to the developments made in the third article. The author(s) may also speculate on the direction of future research in the field. Connections articles aim to set the research in a wide context. Sex differences in crucial aspects of exercise physiology are increasingly recognized among molecular and integrative physiologists. A comprehensive and sex-specific understanding of essential body functions during exercise will eventually provide a sound rationale for implementing effective interventions aimed at improving health and athletic performance. So far, certain intrinsic factors underpinning major sex differences in performance have been established. For instance, evident sex divergences in body size and percentage muscle mass unequivocally contribute to lower strength and power (anaerobic) performance in women. Likewise, structural elements of the aerobic energy system, crucial for endurance performance, are sex specific. Women generally have a smaller heart compared with men, even when normalized by body size. The total amount of fluid that fills the circulatory system, i.e. blood volume, and blood oxygen (O2) carrying capacity are also lower in women (Lundby & Robach, 2015). Collectively considered, women have a lower capacity to deliver O2 to skeletal muscle, a fundamental determinant of aerobic capacity and thereby endurance performance. Nevertheless, women do not apparently show any handicap regarding the last step in the O2 cascade from the lungs into the powerhouse of the cell, i.e. the mitochondria, where O2 is finally consumed to produce ATP, the major ‘energy currency’ molecule. In this regard, we recently determined mitochondrial content and function in skeletal muscle biopsies from healthy women and men matched by aerobic capacity and performance (Montero, Madsen, Meinild-Lundby, Edin, & Lundby, 2018). Women exhibited augmented mitochondrial volume density in skeletal muscle compared with men (Montero et al., 2018). This constitutional characteristic was associated with increased fatty acid and lactate oxidative capacity in skeletal muscle fibres of women (Montero et al., 2018). These findings indicate that women might indeed possess a superior combustion engine in their muscles, at least regarding the capacity to metabolize key energy substrates. The inquiry into sex differences in mitochondrial characteristics was motivated by a consistent finding in exercise physiology. In the 1990s, several research groups noted disparities in energy substrate metabolism between sexes (Horton, Pagliassotti, Hobbs, & Hill, 1998). For a given fitness level and exercise intensity, women rely to a greater extent on fat oxidation (Horton et al., 1998). This metabolic characteristic might attenuate the exercise-induced progressive exhaustion of limited carbohydrate reserves (the amount of which does not differ between sexes), plausibly providing advantages for prolonged endurance performance. Considering the relatively ‘unlimited’ fat reservoir, fuel oxidation during sustained efforts might thus be optimized in women. The question arose whether women's prioritization of fat over carbohydrate oxidation was underlain by a sexual dimorphism in skeletal muscle comprising differences in mitochondrial content and oxidative capacity, which were subsequently revealed in the ‘middle’ article of this ‘Connections’ sequence, as described above (Montero et al., 2018). Recent efforts in this line of investigation have provided new insights. In moderately trained and recreationally active women and men matched by aerobic capacity, the oxidative capacity in isolated skeletal muscle mitochondria normalized by protein levels (intrinsic mitochondrial respiration) was augmented in women (Cardinale et al., 2018). Moreover, moderately trained women presented similar intrinsic mitochondrial respiration compared with long-term highly trained men possessing a one-third higher aerobic capacity (Cardinale et al., 2018). According to these findings, for a given training stimulus female sex might be associated with enhanced skeletal muscle mitochondrial content and function. Concurring with this hypothesis, acute endurance exercise stimulates mitochondrial biogenesis to a greater extent in women than men matched by training status. Taken together, women may need lesser stimuli than men to achieve the mitochondrial adaptations that contribute to an increase in the rate of fat oxidation, which is a fundamental adaptation to endurance training in both sexes (Lundby, Montero, & Joyner, 2017). From a broad perspective regarding basic physical capacities, women do not seem as endowed biologically as men. The widespread view is that biology must constrain women's exercise performance. The evidence outlined herein is thus counterintuitive. In fact, the stereotype of ‘the smaller, weaker sex’ may be overturned. In this regard, the generally smaller body size of women typifies the concept of sexual dimorphism, i.e. intrinsic differences between women and men beyond reproductive organs. Intriguingly, sex differences in skeletal muscle mitochondrial content and function disappear when these are statistically adjusted for body size or leg mass (Montero et al., 2018). Likewise, body size explains sex differences in whole-body fat and carbohydrate oxidation during exercise (Montero et al., 2018). Augmented skeletal muscle mitochondrial density and oxidative capacity have also been observed in parallel with increased reliance on fat oxidation in rodent species, in that females have a smaller body size than males (Colom et al., 2007). Furthermore, among mammalian species, smaller body size is associated with augmented mitochondrial content in skeletal muscle. How body size and related anthropometrical variables could be linked to skeletal muscle mitochondrial phenotype is as yet unclear. Although speculative, the greater dimensions of skeletal muscle fibres in men versus women might contribute to differences in mitochondrial content and function. This hypothetical scenario raises some questions. Could the maternal inheritance of mitochondrial DNA not be attuned perfectly with nuclear genes that determine or influence the size of skeletal muscle fibres in men? Does a ‘genetic ceiling’ in mitochondrial content and function ultimately limit skeletal muscle fat oxidation during exercise in men and in women? These questions can be addressed using current experimental methods. A more challenging inquiry would be to isolate and elucidate which O2-independent factors, if any, explain the reduced performance of women (versus men) during prolonged endurance efforts, despite their enhanced capacity to consume abundant energy substrates per skeletal muscle fibre. Physiology may still hold surprises for those willing to doubt inveterate notions, such as sex separation in certain physical activities and sports. We apologize for all relevant articles that were not cited owing to space restrictions. None declared.

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