Sex Differences in VO2max and the Impact on Endurance-Exercise Performance

t was not until 1984 that women were permitted to compete in the Olympic marathon. Today, more women than men participate in road racing in all distances except the marathon where participation is near equal. From the period of 1985 to 2004, the women's marathon record improved at a rate three times greater than men's. This has led many to question whether women are capable of surpassing men despite the fact that there remains a 10–12% performance gap in all distance events. The progressive developments in sports performance research and training, beginning with A.V. Hill's establishment of the concept of VO 2max, have allowed endurance athletes to continue performance feats previously thought to be impossible. However, even today women are signi - cantly underrepresented in sports performance research. By focusing more research on the female physiology and sex differences between men and women, we can better de ne how women differ from men in adapting to training and potentially use this information to improve endurance-exercise performance in women. The male advantage in endurance-exercise performance has commonly been attributed to their higher VO 2max, even when expressed as mL/kg/min. It is widely known that oxygen delivery is the primary limiting factor in elite athletes when

can better de ne how women differ from men in adapting to training and potentially use this information to improve endurance-exercise performance in women. The male advantage in endurance-exercise performance has commonly been attributed to their higher VO 2max, even when expressed as mL/kg/min. It is widely known that oxygen delivery is the primary limiting factor in elite athletes when it comes to improving VO 2max, but little research has explored the sex differences in oxygen delivery. Thus, the purpose of this review is to highlight what is known about the sex differences in the physiological factors contributing to VO 2max, more speci cally oxygen delivery, and the impacts on performance. Keywords:sex differences; oxygen consumption; athletic performance; exercise physiology 1. Introduction When the modern Olympics were established in 1896, no women were allowed to compete in any event. It wasn't until almost 100 years later, in 1984, that women were rst allowed to compete in the Olympic marathon, still 12 years after rst gaining legal allowance to compete in the Boston and New York marathons. Since then, female participation in the marathon, along with many other endurance events, has increased substantially. In fact, 61% of all road race registrants in 2019 were female, and nearly 50% of participants in marathon races are now women [1]. With increased participation has come marked improvements in performance, as women began to train at volumes and intensities comparable to men. Between 1985 and 2004, women's marathon performance improved at nearly three times the rate of men, leading many to wonder if women would soon catch up to, or even outperform men [2]. That being said, a 13-min gap in world record marathon time still exists between men and women, and across all distance events, there is a consistent gap of ~10–12% between men and women [2,3] (Figure). This suggests that men continue to have a physiological advantage when it comes to endurance sports performance. Since the 1920s, the eld of exercise physiology has grown dramatically, starting with A.V. Hill's interest in the study of athletic performance. It was Hill's introduction of the concept of

there is a consistent gap of ~10–12% between men and women [2,3] (Figure). This suggests that men continue to have a physiological advantage when it comes to endurance sports performance. Since the 1920s, the eld of exercise physiology has grown dramatically, starting with A.V. Hill's interest in the study of athletic performance. It was Hill's introduction of the concept of maximal oxygen consumption (VO2max) and its impact on endurance- exercise performance that has allowed modern researchers to build an extensive conceptual Int. J. Environ. Res. Public Health2022,19, 4946.

Int. J. Environ. Res. Public Health2022,19, 4946 2 of 19 framework explaining the limits of human performance [4]. The progressive developments in sports performance research over the last 100 years have allowed elite athletes to continue to achieve athletic feats beyond what was originally thought possible. However, until recently, most research studies have utilized only male subjects, leaving female athletes largely under-represented in sport and exercise research. In his 2017 review exploring the physiological limitations of female endurance athletes, Dr. Michael Joyner expressed that, “for almost all issues outlined in this paper, there are either fewer or much fewer data on elite women vs. elite men” [3]. Similarly, Costello et al. in 2014 reported that women only made up roughly 35% of research subjects in performance studies [5]. Until the 1980s, it was widely assumed that physiological responses to exercise did not truly differ between men and women [6]. Most current training practices are based on research primarily conducted on men; thus, female athletes are expected to respond like men, creating training standards likely to be unre ective of female athletes' needs [7]. By focusing more research on the female physiology and sex differences between men and women, we can better de ne how women differ from men in adapting to training and use that information to better inform female training methodologies, and potentially increase female endurance-exercise performance. Fortunately, in recent years, increased attention has been placed on the lack of equality between men and women in many areas of society, including research. Over the past 6 years, research initiatives have aimed to include more female subjects in clinical trial research and emphasize physiological differences between men and women [8]. These are important steps, but signi cantly more research speci c to women is warranted.Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 2 of 20 Figure 1. Reprinted with permission from Ref. [3]. 2017 The Physiological Society. History of world records in the marathon for men and women, modified slightly to show current world record times. The impact of changes in training and culture has helped

c to women is warranted.Int. J. Environ. Res. Public Health 2022, 19, x FOR PEER REVIEW 2 of 20 Figure 1. Reprinted with permission from Ref. [3]. 2017 The Physiological Society. History of world records in the marathon for men and women, modified slightly to show current world record times. The impact of changes in training and culture has helped with the steep improvement in women’s marathon record times through 2005. Physiological sex differences are primarily responsible for the gap that still exists between men’s and women’s times in all distances of individual endurance events, although cultural and training differences still exist. Since the 1920s, the field of exercise physiology has grown dramatically, starting with A.V. Hill’s interest in the study of athletic performance. It was Hill’s introduction of the concept of maximal oxygen consumption (VO 2max) and its impact on endurance-exercise performance that has allowed modern researchers to build an extensive conceptual frame- work explaining the limits of human performance [4]. The progressive developments in sports performance research over the last 100 years have allowed elite athletes to continue to achieve athletic feats beyond what was originally thought possible. However, until re- cently, most research studies have utilized only male subjects, leaving female athletes largely under-represented in sport and exercise research. In his 2017 review exploring the physiological limitations of female endurance athletes, Dr. Michael Joyner expressed that, “for almost all issues outlined in this paper, there are either fewer or much fewer data on elite women vs. elite men” [3]. Similarly, Costello et al. in 2014 reported that women only made up roughly 35% of research subjects in performance studies [5]. Until the 1980s, it was widely assumed that physiological responses to exercise did not truly differ between men and women [6]. Most current training practices are based on research primarily con- ducted on men; thus, female athletes are expected to respond like men, creating training standards likely to be unreflective of female athletes’ needs [7]. By focusing more research on the female physiology and sex differences between men and women, we can better define how women differ

men and women [6]. Most current training practices are based on research primarily con- ducted on men; thus, female athletes are expected to respond like men, creating training standards likely to be unreflective of female athletes’ needs [7]. By focusing more research on the female physiology and sex differences between men and women, we can better define how women differ from men in adapting to training and use that information to better inform female training methodologies, and potentially increase female endurance- exercise performance. Fortunately, in recent years, increased attention has been placed on the lack of equality between men and women in many areas of society, including research. Over the past 6 years, research initiatives have aimed to include more female subjects in clinical trial research and emphasize physiological differences between men and women [8]. These are important steps, but significantly more research specific to women is war- ranted. Figure 1. Reprinted with permission from Ref. [3]. 2017 The Physiological Society. History of world records in the marathon for men and women, modi ed slightly to show current world record times. The impact of changes in training and culture has helped with the steep improvement in women's marathon record times through 2005. Physiological sex differences are primarily responsible for the gap that still exists between men's and women's times in all distances of individual endurance events, although cultural and training differences still exist. 1.1. Maximal Oxygen Consumption (VO2max) The male advantage in endurance-exercise performance has been primarily attributed to the sex difference observed in VO2max[4], a key determinant of aerobic performance. Even truly elite women have VO2maxvalues ~10% lower than those seen in men of similar elite status when expressed as mL/kg/min [4]. Whole-body oxygen consumption (VO2) increases with increasing exercise intensity as a consequence of greater oxygen demand from the exercising muscles. This increase in oxygen demand occurs because almost all the energy (i.e., ATP) utilized during an endurance-exercise performance (aerobic exercise) will be resynthesized in the mitochondria through oxidative metabolism [9]. With this rise in oxygen consumption, concurrent increases in a number of cardiovascular and respiratory

exercise intensity as a consequence of greater oxygen demand from the exercising muscles. This increase in oxygen demand occurs because almost all the energy (i.e., ATP) utilized during an endurance-exercise performance (aerobic exercise) will be resynthesized in the mitochondria through oxidative metabolism [9]. With this rise in oxygen consumption, concurrent increases in a number of cardiovascular and respiratory

Int. J. Environ. Res. Public Health2022,19, 4946 3 of 19 variables occur such as heart rate, ventilation, and stroke volume. Essentially, we can think of VO2as the ability for oxygen delivery to, and utilization by, the muscles during exercise. As intensity approaches maximal levels, VO2reaches a plateau unaffected by further increases in exercise intensity [10]; this plateau is termed VO2max. VO2maxrepresents the maximal rate at which ATP can be resynthesized through aerobic pathways and creates a limitation to exercise tolerance [11]. VO2maxis determined by the product of maximal cardiac output, which can be broken down into stroke volume times heart rate, and the maximal arterio-venous O2content difference (Da-vO2). The limitation of oxygen delivery to the exercising muscles by “central” hemodynamic factors is most commonly considered the limiting factor in elite athletes to further increases in VO2at extremely high exercise intensities [12]. The central factors involved in O2delivery during exercise include pulmonary ventilation, diffusion across the pulmonary capillary membrane, cardiac output, and hemoglobin mass, in addition to peripheral factors such as skeletal muscle blood ow, and diffusion of O2from the microcirculation into the muscle [9]. Elite female athletes' inability to match the high oxygen consumption of their male counterparts is often attributed to those central factors—women typically have smaller hearts, lungs, and lower hemoglobin mass than men—limiting their capacity to deliver oxygen to the working muscles. 1.2. Other Determinants of Endurance-Exercise Performance VO2maxalone cannot discriminate the performance capabilities in groups of endurance athletes that have similarly high VO2maxvalues [11]. Rather, there are a number of other physiological factors that impact the inter-individual variability between elite endurance athletes. These include running economy, lactate threshold, and critical power, and com- bined help to determine the average speed that an athlete can sustain during a distance event [11]. Which factors have the biggest impact in any given distance of race will depend on many factors, including pacing strategies. 1.2.1. Running Economy Running economy describes the oxygen cost of running at a certain speed or dis- tance and can vary by as much as 30–40% amongst elite individuals [11,13]. The basis of these inter-individual differences

a distance event [11]. Which factors have the biggest impact in any given distance of race will depend on many factors, including pacing strategies. 1.2.1. Running Economy Running economy describes the oxygen cost of running at a certain speed or dis- tance and can vary by as much as 30–40% amongst elite individuals [11,13]. The basis of these inter-individual differences in running economy remains somewhat elusive to researchers [14] but are known to be impacted by both physiological and anthropometric factors such as a high type I skeletal muscle proportion, increased mitochondrial volume, biomechanical factors, and breathing economy [15]. An athlete with a good running econ- omy can utilize a lower percentage of their VO2maxfor a given running velocity, reducing both glycogen utilization and reliance on anaerobic metabolism during an endurance com- petition [11]. While VO2maxhas been shown to remain fairly consistent over time in elite athletes, the running economy will often improve throughout their athletic careers [11]. When using anthropometric scaling to body mass, recent studies have shown that women have a better running economy compared to men [16,17]. Mendonca et al. showed that when comparing men and women with similar percent differences from predicted VO2max, women showed better running economy consistently across a broad spectrum of submax- imal running speeds [16]. Despite a 25% difference in VO2maxbetween the sexes in this study, maximal aerobic speed was only 18% different, indicating that running economy could partially compensate for women's reduced VO2max[16]. Stoa et al. also showed that, when scaled for body weight, women showed a 9% better oxygen cost of running compared to men. This study included long-distance runners with performance levels ranging from elite to regional [17]. 1.2.2. Lactate Threshold The lactate threshold represents the highest intensity of exercise that can be performed before lactate removal exceeds lactate production, resulting in blood lactate accumulation during exercise. Exercise near the lactate threshold can be sustained for >2 h with blood

exercise that can be performed before lactate removal exceeds lactate production, resulting in blood lactate accumulation during exercise. Exercise near the lactate threshold can be sustained for >2 h with blood

Int. J. Environ. Res. Public Health2022,19, 4946 4 of 19 lactate concentrations remaining stable and only slightly elevated [11]. The lactate threshold has been shown to improve with endurance training, with these improvements attributed to increased muscle lactate transport capacity and a higher proportion of type I skeletal muscle bers, which both slow the accumulation of lactate in the blood [15,18]. The lactate threshold is often expressed as a fraction of VO2max[11], and elite athletes are capable of sustaining 80–90% of their VO2maxfor long-duration exercise with only slight increases in blood lactate [4]. The lactate threshold has previously been shown to be highly correlated with performance in distance running events such as the marathon [4], such that for two hypothetical athletes with a similar VO2maxand similar running economy, the athlete with the lactate threshold closer to their VO2maxwould be expected to perform better. Along these lines, Stoa et al. [17] found slightly higher lactate thresholds in women compared to men (85% vs. 83% of VO2max). However, the authors noted that with higher VO2maxin the men, women still had lower running velocities at the lactate threshold [17]. (They observed a similar pattern of higher VO2maxbut similar lactate threshold resulting in higher running velocities at lactate threshold when comparing the elite, national, and recreational athletes.) 1.2.3. Critical Power While the concept of the lactate threshold has been considered by exercise physi- ologists since the late 1970s and has signi cant time to work its way into the coaching vernacular, critical power has more recently emerged as a robust physiological model. Crit- ical power represents the greatest metabolic rate that results in “wholly oxidative” energy utilization [19]. In terms of intensity, critical power is located above the lactate threshold and denotes the threshold between heavy and severe intensity exercise. Heavy exercise represents exercise that can be sustained for long durations while severe intensity exercise is that in which exercise tolerance becomes predictably limited [19]. Heavy intensity ex- ercise is characterized by elevated but steady levels of blood lactate concentrations and VO2; however, once the critical power threshold is crossed, blood lactate and VO2steadily

between heavy and severe intensity exercise. Heavy exercise represents exercise that can be sustained for long durations while severe intensity exercise is that in which exercise tolerance becomes predictably limited [19]. Heavy intensity ex- ercise is characterized by elevated but steady levels of blood lactate concentrations and VO2; however, once the critical power threshold is crossed, blood lactate and VO2steadily increase until the exercise is terminated. Severe intensity exercise is also characterized by pronounced reductions in phosphocreatine content and pH, and increased lactate and inorganic phosphate concentrations within the exercising muscle [20]. The ability to sustain a given submaximal power output during long-duration events of greater than 1–2 h will be determined by critical power [20–24] but will be epiphenomenally related to lactate threshold (at least under many exercise conditions). During exercise tasks where whole-body oxygen delivery is not required, such as single-limb isometric contractions, the power-duration relationship has been shown to differ between men and women [25]. Women exhibit greater fatigue resistance due to a greater proportional area of type I bers and capillary density in the knee extensors. Therefore, when completing tasks that are not dependent on the cardiopulmonary system, women show a greater capacity for oxidative metabolism and fatigue resistance [26]. However, when considering whole-body exercise, factors that in uence oxygen transport, such as ventilation, cardiac output, and hemoglobin have a signi cant in uence [26]. When comparing the power–duration relationship between men and women during cycling, Ansdell et al. found no differences in women compared to men for relative critical power (74% vs. 72% of maximal power) [25], but as in the case above for lactate threshold, this translated into a lower absolute critical power. Thus, it is likely that when considering whole-body exercise, the female advantage disappears. Although these additional parameters play an important role in impacting endurance- exercise performance across elite athletes, VO2maxis thought to be the biggest factor impacting sex differences in performance. Thus, the purpose of this review is to explore the current research investigating sex differences in the physiological factors contributing to VO2max, speci cally those that determine oxygen delivery, and

The review explores how physiological differences affect endurance performance between sexes.