Joyner, Michael J

There is a context-dependent trade-off in body size of elite runners, such that smaller body sizes are observed among longer distance runners. However, it is unclear whether this trade-off in body size is observed in other Olympic sports, such as cycling and swimming. To understand the association between body size and athletic competition, we examined metrics of body size from male and female Olympic athletes competing in swimming, running, and cycling. We collected standard anthropometrics (height, mass, body mass index (BMI), and body surface area) of elite male and female athletes competing in the London 2012 Summer Olympics from a public repository. Anthropometric data were compared between sexes (male and female); between sports (swimming, running, and cycling); and between distances within sports (shorter and longer distance). Males were taller ( P < 0.001), heavier ( P < 0.001), and had a larger BMI ( P < 0.001) compared to females. Relative to athletes competing in longer distance events, athletes competing in shorter distance were generally taller (running: P < 0.001, swimming: P ≤ 0.014) and heavier (running: P < 0.001, swimming: P = 0.002 (males) and P = 0.148 (females), cycling: P < 0.001) for both males and females. Height was not different between shorter and longer distance cyclists. There was a trade-off between body size and distance for each of the three Olympics sports, such that smaller athletes were observed in longer distance events. Although there were large sex-based differences in body size, similar trade-offs in size and event were observed for both males and females. These data suggest that there is an optimal combination of skeletal muscle mass and body size to optimize movement economy that is generally preserved across different modes of human locomotion.

AbstractMenopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium‐dependent, endothelium independent and β2‐adrenergic receptor‐induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium‐dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β2‐adrenergic receptor agonist) with and without concurrent infusion of 17β‐oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post‐menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β‐oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. imageKey points Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause‐associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

AbstractIn 1991, I published a physiological model of marathon running performance. My model predicted that it might be possible for a human to run the marathon in less than 2 hours. In this article, I review the genesis of my thinking at that time, share my perspective about what has changed over the last 30 plus years, and speculate about what the future might hold.

ABSTRACTThis essay summarizes and integrates my experiences and observations—starting in the middle 1970s—as an athlete, scientist interested in human performance, biomedical researcher, and “expert,” who sometimes advises athletes, coaches, and sports policy‐makers. In this context, my focus has been primarily on endurance sports and five concepts underpin what I have learned over the last 50 years. (1) The “competitive significance principle” whereby athletes, coaches, and policy‐makers are frequently interested in performance improvements of 1% or less. This is especially true at the elite level. (2) Science frequently explains what coaches and athletes have already discovered in the field. (3) Many science‐based performance improvements have reduced the energy cost of moving a given speed. (4) Varied and eclectic training programs have been used by elite athletes with similar performance outcomes. (5) A few things that are actionable matter. Coaches, athletes, and administrators should focus their efforts on what is actionable.

Sex differences in sports performances continue to attract considerable scientific and public attention, driven in part by high profile cases of: 1) biological male (XY) athletes who seek to compete in the female category after gender transition, and 2) XY athletes with medical syndromes collectively known as disorders or differences of sex development (DSDs). In this perspective, we highlight scientific evidence that informs eligibility criteria and applicable regulations for sex categories in sports. There are profound sex differences in human performance in athletic events determined by strength, speed, power, endurance, and body size such that males outperform females. These sex differences in athletic performance exist before puberty and increase dramatically as puberty progresses. The profound sex differences in sports performance are primarily attributable to the direct and indirect effects of sex-steroid hormones and provide a compelling framework to consider for policy decisions to safeguard fairness and inclusion in sports.

Background : Maintaining oxygen delivery during conditions of hypoxia is important, particularly for patients with hemoglobinopathies.Evidence in comparative physiology indicates that high hemoglobin-oxygen (Hb-O2) affinity serves as a beneficial hematological adaptation to chronic hypoxia exposure. The improved hypoxia tolerance is likely due to an increase in arterial oxygen saturation with high Hb-O2 affinity. However, the relationship between high Hb-O2 affinity and hypoxia tolerance in humans is not well understood. Etavopivat is a potent, selective, once-daily, oral activator of the red blood cell (RBC) pyruvate kinase isozyme (PKR), with a half-life of ~13 hours, under investigation for the treatment of sickle cell disease (SCD) and other hematological conditions. Etavopivat has a multimodal mechanism of action in RBCs by decreasing 2,3-diphosphoglycerate (2,3-DPG) levels to increase Hb-O2 affinity and increasing adenosine triphosphate (ATP) levels to improve RBC health. In Phase 1 trials etavopivat increased Hb-O2 affinity in healthy volunteers (HVs; Forsyth et al. Clin Pharmacol Drug Dev 2022) and patients with SCD (Saraf et al. Blood Adv 2024) in room air. Aim: To investigate arterial oxygenation changes with etavopivat under conditions of moderate and severe hypoxia in HVs. Methods: HVs visited the laboratory for assessments at baseline and following 7 days of etavopivat exposure (400 mg once daily). Participants completed rhythmic handgrip exercises (rest, 10% and 20% maximum voluntary contraction [MVC]) during graded hypoxic exposure, breathing room air (21% O2), moderate hypoxic gas (15% O2), and severe hypoxic gas (10% O2), resulting in acute duration (~12 minutes) of exposure to each level of hypoxia. Hb-O2 affinity was assessed by partial pressure of oxygen at 50% Hb saturation (P50), measured using dual-wavelength spectrophotometry at a standardized pH (~7.4) and temperature (37 ºC). Arterial catheterization was used to collect samples for fractional oxygen saturation (FO2Hb) and Hb and to measure arterial blood pressure. Blood gases were analyzed after 5 minutes of resting exposure to each inspirate, then ~2.5 minutes after commencing each of the 3-minute handgrip exercises (10% followed by 20% MVC). Liquid chromatography-tandem mass spectrometry was used to evaluate 2,3-DPG and ATP levels in whole blood. Data for FO2Hb and heart rate were analyzed using separate repeated measures 2 (treatment) x 3 (intensity) ANOVA for each inspirate and all other hematological data pre vs post etavopivat were analyzed using paired-sample t-tests. Statistical significance was set at P&lt;0.05. Data presented are mean ± standard deviation. Results: Sixteen HVs (five women) aged 32 ±8 years were enrolled. After 7 days of oral once-daily 400 mg etavopivat, P50 decreased from 28.6 ±1.6 at baseline to 24.8 ±1.3 mmHg (P&lt;0.001). Hb concentration remained unchanged from baseline (14.6 ±1.1 g/dL), post etavopivat (14.5 ±1.1 g/dL; P&gt;0.05). FO2Hb at rest decreased from 96.0% ±0.6 under normal oxygen conditions to 74.6% ±6.7 during severe hypoxic exposure; however, this decrease in FO2Hb was mitigated post etavopivat exposure (79.7% ±5.2, P&lt;0.001). A similar mitigation of the FO2Hb decrease was observed during the handgrip exercise (20% MVC, P&lt;0.001). Concentrations of 2,3-DPG decreased and RBC ATP increased following etavopivat exposure during both normoxia and moderate hypoxia (P&lt;0.001). Mean arterial pressure was lower post etavopivat exposure under normoxia, but not during moderate or severe hypoxia. Heart rate showed no change post etavopivat exposure during normoxia and hypoxia (P&gt;0.50). Etavopivat was well tolerated with no unexpected adverse events reported. Conclusions: Etavopivat enhanced FO2Hb during brief hypoxic episodes with an apparent relationship to hypoxia severity for which the greatest improvements were observed at more severe hypoxic exposure. In SCD, high Hb-O2 affinity is beneficial for maintaining Hb ‘R’ state, thereby reducing the risk of polymerization and associated sickling. Increased Hb-O2 affinity, together with maintenance of a high FO2Hb under hypoxic conditions, demonstrates etavopivat's ability to promote oxygen exchange and subsequent delivery. Together with projected improvement of RBC health, also achieved via PKR activation, this indicates a potential clinical benefit with etavopivat for hemoglobinopathies and beyond.