Mitochondrial basis for sex-differences in metabolism and exercise performance

There are many physiological benefits of being a woman. This is most obvious in the simplest measures of “physiological function”: survival rate and lifespan (1, 10, 15). Yet, longevity benefits conferred by the female sex do not appear to translate to whole body exercise performance. For example, women are slower than men in endurance events with distances ≤42 km (or 26.2 miles), i.e., regular marathon. Metabolism is among the physiological factors that contribute to survival and exercise performance. Several studies have shown sex differences in metabolism at rest and during exercise. This is particularly interesting because mitochondria take center stage in metabolic homeostasis. The notion of sex differences in mitochondrial function and metabolic homeostasis is now strengthened by the study by Miotto et al. (12) that appears in Am J Physiol-Regulatory, Integrative and Comparative Physiology. The study is an important step toward understanding mechanisms underlying sex differences in metabolism, with potential implications for exercise performance. Among several relevant findings, the study by Miotto and colleagues shows that women skeletal muscle have 1) higher inhibition of mitochondrial fatty acid metabolism by malonyl-CoA, 2) greater abundance of the fatty acid transporter CD36, and 3) lower ADP sensitivity of mitochondrial respiration.

Malonyl-CoA inhibits mitochondrial transport of fatty acids and is particularly important in the interplay between lipid and carbohydrate metabolism (17). A higher sensitivity of mitochondrial fatty acid oxidation to malonyl-CoA likely contributes to elevated rates of free fatty acid (FFA) incorporation into triglycerides at rest and postprandial states as well as greater percentage of body fat in women compared with men (21). From an evolutionary perspective, it makes sense. In conditions of unpredictable food supply, higher inhibition of fatty acid oxidation by malonyl-CoA can be beneficial for survival and evolutionary success as females must store energy for themselves and a potential pregnancy (11). In the context of a high-fat and sugar diet with sedentarism, higher mitochondrial sensitivity to malonyl-CoA is an attractive candidate mechanism for the higher incidence of obesity and metabolic syndrome that has been reported in women (reviewed in 11).

During exercise, the regulation of lipid metabolism largely shifts from malonyl-CoA to the fatty acid transport protein CD36 (6, 17). Muscle contraction signals the translocation of CD36 to plasma and mitochondrial membranes, which facilitates FFA transport and metabolism (13). In mice, muscle-specific overexpression of CD36 resulted in three- to fourfold higher fatty acid oxidation by contracting muscle (6). Thus, higher abundance of CD36, as shown by Miotto et al. (12) and others (9), may result in greater membrane translocation of the protein upon contraction and heighten lipid metabolism during exercise. Consistent with this notion, women have higher lipid oxidation during submaximal exercise (3, 16, 18).

The finding of lower ADP sensitivity of mitochondrial respiration in women by Miotto and colleagues is novel and may have relevance for sex differences in exercise performance. In 1992, Whipp and Ward predicted that women would outrun men after the year of 1998 (25). Twenty years after the “cross-over” mark predicted by Whipp and Ward, women remain slower than men in traditional endurance events (for details on sex differences in exercise performance see recent reviews in Refs. 4, 5, and 8). Maximal O₂ uptake is an important determinant of exercise performance in endurance events (7, 8). An individual’s V̇o_2max is determined by maximal O₂ transport and diffusion as well as mitochondrial respiration (22). Maximal mitochondrial respiration of men and women muscles was similar in gastrocnemius (19) and vastus lateralis (12). Measurements of maximal respiration provide insights into mitochondrial content, but the significance for function is limited to high concentrations of ADP (i.e., in the mM range). Importantly, Miotto et al. (12) found lower muscle mitochondrial O₂ consumption in women compared with men at a physiologically relevant concentrations of ADP (100 µM). This observation implies that for exercise performed at matched workloads, female muscles require higher [ADP] to achieve the same V̇o₂ compared with males (27). Indeed, separate studies have shown that females have a similar O₂ cost of work or running economy (5, 24) but higher muscle accumulation of ADP than males (26). This metabolic profile mandates higher levels of intracellular phosphate, which impairs cross-bridge function and calcium release that lead to muscle fatigue (2, 14, 23). Several physiological factors determine sex differences in fatigability (4). However, with matched workloads and all else being equal, a lower ADP sensitivity of mitochondrial respiration will likely contribute to women being slower than men in endurance events.

Interestingly, the profile described by Miotto et al. (12) occurs despite women having higher levels of 17β-estradiol that lowers mitochondrial membrane viscosity (20). A lower membrane viscosity creates a more fluid lipid bilayer, which facilitates movement and function of membrane proteins. Based on the functional differences reported (12), it is reasonable to ask: Is mitochondrial membrane viscosity lower in men than women? If so, what are the mechanisms underlying sex differences in membrane viscosity, malonyl-CoA inhibition of fatty acid oxidation, and ADP sensitivity of respiration? The study shows that differences in protein content are not involved, which suggests that posttranslational modifications or enzyme allosteric regulation are critical mediators of sex differences in mitochondrial function. Future studies should also determine sex differences in mitochondrial protein content and function with endurance training and aging. Overall, the findings by Miotto and colleagues provide a foundation at the protein and organelle level to understand sex differences in metabolism at rest and during exercise.

GRANTS

L. Ferreira’s research is funded by National Heart, Lung, and Blood Institute Grant R01-HL130318.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

L.F.F. drafted manuscript; L.F.F. edited and revised manuscript; L.F.F. approved final version of manuscript.