A Personal Biography of a Physiological Misnomer: The Anaerobic Threshold.

In 1973 Wasserman, Whipp, Koyal, and Beaver published a groundbreaking study titled "Anaerobic threshold and respiratory gas analysis during exercise". At that time, respiratory gas analysis and laboratory computers had evolved such that more advanced respiratory exercise physiology studies were possible. The initial publications from this group on the onset of anaerobic metabolism in cardiac patients, the first breath-by-breath VO2 system, the first description of the anaerobic threshold, and then later new methods to detect the anaerobic threshold have been and continue to be highly cited. In fact, their 1973 anaerobic threshold paper is the sixth and their 1986 paper is the second most cited paper ever published in the Journal of Applied Physiology. The anaerobic threshold concept has also generated>5500 publications with the rates increasing over time. The publication of two papers that help to refute the "anaerobic" explanation for this phenomenon had no effect on the rates of citations of the original anaerobic threshold papers or the number of anaerobic threshold papers published since. Thus, despite now substantial evidence refuting the proposed anaerobic mechanisms underlying this phenomenon, these papers continue to be highly influential in the discipline of exercise physiology and, perhaps even more explicitly, clinical exercise physiology.

Circulating MicroRNA Responses to Postprandial Lipemia with or without Prior Exercise.

Repeated exposure to a high-fat meal triggers inflammation and oxidative stress, contributing to the onset of cardiometabolic diseases. Regular exercise prevents cardiometabolic diseases and a prior bout of acute endurance exercise can counteract the detrimental cardiovascular effects of a subsequent high-fat meal. Circulating microRNAs (ci-miRs) are potential mediators of these vascular effects through regulation of gene expression at the posttranscriptional level. Therefore, we investigated the expression of ci-miRs related to vascular function (miR-21, miR-92a, miR-126, miR-146a, miR-150, miR-155, miR-181b, miR-221, miR-222) in plasma from healthy, recreationally to highly active, Caucasian adult men after a high-fat meal with (EX) and without (CON) a preceding bout of cycling exercise. Ci-miR-155 was the only ci-miR for which there was a significant interaction effect of high-fat meal and exercise (p=0.050). Ci-miR-155 significantly increased in the CON group at two (p=0.007) and four hours (p=0.010) after the high-fat meal test, whereas it significantly increased in the EX group only four hours after the meal (p=0.0004). There were significant main effects of the high-fat meal on ci-miR-21 (p=0.01), ci-miR-126 (p=0.02), ci-miR-146a (p=0.02), ci-miR-181b (p=0.02), and ci-miR-221 (p=0.008). Collectively, our results suggest that prior exercise does not prevent high-fat meal-induced increases in vascular-related ci-miRs.

Race-specific changes in endothelial inflammation and microRNA in response to an acute inflammatory stimulus.

Both aberrant vascular reactivity to acute cardiovascular stress and epigenetic mechanisms such as microRNA (miR) may underlie the increased propensity for African Americans (AA) to develop cardiovascular disease. This study assessed racial differences in acute induced endothelial inflammation and related miRs. Cultured human umbilical vein endothelial cells (HUVECs) derived from AA and Caucasian Americans (CA) were exposed to influenza vaccine to determine changes in inflammatory markers, endothelial nitric oxide synthase (eNOS), and miR expression/release. Endothelial function [flow-mediated dilation (FMD)], circulating IL-6, and circulating miR were also measured in young, healthy AA and CA individuals before and after receiving the influenza vaccine. There were no significant racial differences in any parameters at baseline. The vaccine induced increases in IL-6 release (24%, P = 0.02) and ICAM-1 mRNA (40%, P = 0.03), as well as reduced eNOS mRNA (24%, P = 0.04) in AA HUVECs, but not in CA HUVECs (all P > 0.05). Intracellular levels of anti-inflammatory miR-221-3p and miR-222-3p increased specifically in CA HUVECs (72% and 53%, P = 0.04 and P = 0.06), whereas others did not change in either race. HUVEC secretion of several miRs decreased in both races, whereas the release of anti-inflammatory miR-150-5p was decreased only by AA cells (-30%, P = 0.03). In individuals of both races, circulating IL-6 increased approximately twofold 24 h after vaccination (both P < 0.01) and returned to baseline levels by 48 h, whereas FMD remained unchanged. Although macrovascular function was unaffected by acute inflammation in AA and CA individuals, AA endothelial cells exhibited increased susceptibility to acute inflammation and unique changes in related miR.NEW & NOTEWORTHY Used as an acute inflammatory stimulus, the influenza vaccine induced an inflammatory response and decreased eNOS gene expression in endothelial cells derived from African Americans, but not Caucasian Americans. Race-specific changes in intracellular expression and release of specific microRNAs also occurred and may contribute to an exaggerated inflammatory response in African Americans. In vivo, the vaccine caused similar systemic inflammation but had no effect on endothelial function or circulating microRNAs in individuals of either race.

Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells.

Exercise training has various benefits on cardiovascular health, and circulating angiogenic cells have been proposed as executing these changes. Work from the late 1990s supported an important role of these circulating post-natal cells in contributing to the maintenance and repair of the endothelium and vasculature. It was later found that circulating angiogenic cells were a heterogenous population of cells and primarily functioned in a paracrine manner by adhering to damaged endothelium and releasing growth factors. Many studies have discovered novel circulating angiogenic cell secreted proteins, microRNA and extracellular vesicles that mediate their angiogenic potential, and some studies have shown that both acute and chronic aerobic exercise training have distinct benefits. This review highlights work establishing an essential role of secreted factors from circulating angiogenic cells and summarizes studies regarding the effects of exercise training on these factors. Finally, we highlight the various gaps in the literature in hopes of guiding future work.

Greater Semantic Memory Activation After Exercise Training Cessation in Older Endurance-Trained Athletes.

PURPOSE: To examine the effects of a 10-day exercise-training cessation on semantic memory functional activation in older distance runners. METHODS: Ten master runners (62.6 ± 7.0 years) with a long-term endurance-training history (29.0 ± 6.0 years) underwent a 10-day training cessation. Before and immediately after the training cessation, semantic memory activation was measured during the famous name recognition task, using functional magnetic resonance imaging. RESULTS: The 10-day training cessation resulted in greater semantic memory activation in three brain regions, including the left inferior frontal gyrus, parahippocampal gyrus, and inferior semilunar lobule. The 10-day training cessation did not significantly alter famous name recognition task performance. CONCLUSIONS: The findings demonstrate that even a relatively short period without exercise training alters the functional activation patterns of semantic memory-related neural networks. Increased semantic memory activation after training cessation may indicate reduced neural efficiency during successful memory retrieval.

Circulating microparticle concentrations across acute and chronic cardiovascular disease conditions.

Concentrations of different circulating microparticles (MPs) may have clinical and physiological relevance to cardiovascular disease pathologies. PURPOSE: To quantify plasma concentrations of CD31+/CD42b-, CD62E+, and CD34+ MPs across healthy individuals and those with coronary artery disease (CAD) or acute cardiovascular events (non-ST elevation myocardial infarction (NSTEMI)). Fasted blood was obtained from CAD patients (n = 10), NSTEMI patients (n = 13), and healthy older men (n = 15) 60-75 years old. METHODS: CD31+/CD42b-, CD62E+, and CD34+ MPs were isolated from plasma and quantified using flow cytometry. Relationships between MP subtypes, fasting blood lipids, blood glucose, blood pressure, body mass index, and total number of medications were assessed. RESULTS: Concentrations of CD31+/CD42b- MPs were significantly lower in CAD and NSTEMI subjects compared with healthy individuals (p = .02 and .003, respectively). No differences between groups were found for CD62E+ or CD34+ MPs (p > .05 for both). Surprisingly, among all variables assessed, only CD62E+ MP concentrations were positively correlated with triglyceride levels (p = .012) and inversely correlated with SBP (p = .03). CONCLUSIONS: Our findings provide support for the use of different MP subtypes, specifically CD31+/CD42b- MPs, as a potential biomarker of cardiovascular disease. Importantly, results from this study should be looked at in adjunct to previous MP work in CVD conditions as a way of highlighting the complex interactions of variables such as comorbid conditions and medications on MP concentrations.

Sex-specific alterations in blood-borne factors in physically inactive individuals are detrimental to endothelial cell functions.

Mechanisms underlying the protective effects of both habitual endurance exercise and the female sex on vascular function are incompletely understood. Blood-borne circulating factors, such as circulating microRNAs (ci-miRs), may partially explain these effects. Blood samples were obtained from young, healthy men and women who either habitually performed endurance exercise (endurance trained) or were relatively inactive (sedentary). Women were tested during the early follicular phase of the menstrual cycle or the placebo pill phase of oral contraceptive to control for estrogen. Cultured human umbilical vein endothelial cells (HUVECs) were exposed to participants' serum in migration, proliferation, and reactive oxygen species (ROS) assays. Real-time quantitative polymerase chain reaction was used to quantify an initial array of 84 cardiovascular disease (CVD)-related ci-miRs, followed by validation of 10 ci-miRs. All participants were devoid of traditional CVD risk factors, and circulating estradiol concentration was not different between groups. Serum of endurance-trained women induced greater HUVEC migration compared with serum of sedentary women. HUVEC ROS production was greater in response to serum of sedentary men compared with serum of endurance-trained men and sedentary women. There were sex effects on the levels of nine ci-miRs, with greater levels in men, while ci-miRs-140-5p and 145-5p were also higher in sedentary compared with endurance-trained men and/or women. In a sex-specific manner, habitual endurance exercise was associated with beneficial effects of serum on HUVECs. Thus, alterations in circulating factors may contribute to the protective effects of habitual endurance exercise on vascular health. Additionally, sex had a greater impact than habitual activity level on the levels of vascular-related ci-miRs.NEW & NOTEWORTHY Serum from sedentary women caused impaired endothelial migration, whereas serum from sedentary men elicited increased endothelial reactive oxygen species production as compared with serum from their endurance-trained counterparts. Select CVD-related circulating microRNAs (ci-miRs) were higher in men than women, while ci-miRs-140-5p and 145-5p were also higher in sedentary versus trained men and/or women. Our data suggest that alterations in circulating factors may contribute to the protective effects of habitual exercise and sex on vascular health.

Changes in circulating microRNA and arterial stiffness following high-intensity interval and moderate intensity continuous exercise.

High-intensity interval (HII) exercise elicits distinct vascular responses compared to a matched dose of moderate intensity continuous (MOD) exercise. However, the acute effects of HII compared to MOD exercise on arterial stiffness are incompletely understood. Circulating microRNAs (ci-miRs) may contribute to the vascular effects of exercise. We sought to determine exercise intensity-dependent changes in ci-miR potentially underlying changes in arterial stiffness. Ten young, healthy men underwent well-matched, 30-min HII and MOD exercise bouts. RT-qPCR was used to determine the levels of seven vascular-related ci-miRs in serum obtained immediately before and after exercise. Arterial stiffness measures including carotid to femoral pulse wave velocity (cf-PWV), carotid arterial compliance and ß-stiffness, and augmentation index (AIx and AIx75) were taken before, 10min after and 60min after exercise. Ci-miR-21-5p, 126-3p, 126-5p, 150-5p, 155-5p, and 181b-5p increased after HII exercise (p < .05), while ci-miR-150-5p and 221-3p increased after MOD exercise (p = .03 and 0.056). One hour after HII exercise, cf-PWV trended toward being lower compared to baseline (p = .056) and was significantly lower compared to 60min after MOD exercise (p = .04). Carotid arterial compliance was increased 60min after HII exercise (p = .049) and was greater than 60min after MOD exercise (p = .02). AIx75 increased 10 min after both HII and MOD exercise (p < .05). There were significant correlations between some of the exercise-induced changes in individual ci-miRs and changes in cf-PWV and AIx/AIx75. These results support the hypotheses that arterial stiffness and ci-miRs are altered in an exercise intensity-dependent manner, and ci-miRs may contribute to changes in arterial stiffness.

The unfortunately long life of some retracted biomedical research publications.

In 2005 the scientific misconduct case of a noted researcher concluded with, among other things, the retraction of 10 papers. However, these articles continue to be cited at relatively high rates. The objectives of this paper are: 1) to track the retraction process of these papers, 2) to assess the impact of retraction on subsequent citation rates of these papers, and 3) to compare the citation history of these retracted articles and five other high-profile retraction cases. For objective 1, all five articles to be retracted were retracted and of the four to be corrected, two were retracted and two were corrected. Eight PubMed and journal sites were identified where retraction messages could be conveyed; the number of retraction messages averaged 3.4 ± 2.5 for these nine articles. For objective 2, an absolute "cleansing" did not occur. While it initially appears there was a relative "cleansing," as citation rates for these articles did decrease after retraction, the reductions in citation rates for these articles (-28%) were the same as those for matched nonretracted publications both by the same author (-28%) and by another investigator (-29%) over the same time frame. Relative to objective 3, the results for this case are quite different from the five other cases assessing this issue, perhaps because of this investigator's "citation inertia" as a result of the small percentage of his papers that were retracted and the large number of citations to the articles before their retraction and to all of his published articles.NEW & NOTEWORTHY The scientific misconduct and fraud case of a noted exercise physiology researcher was concluded ~15 yr ago, and one the of the results was the retraction of 10 published manuscripts. However, based on a number of comparisons to that same author's and another investigator's citation histories for similar articles, the citation histories for these retracted articles appear to not have been affected whatsoever in the subsequent 15 yr.

The effects of moderate and high-intensity exercise on circulating markers of endothelial integrity and activation in young, healthy men.

Endothelial function typically exhibits a hormetic response to exercise. It is unknown whether endothelial damage occurs in response to acute exercise and could be a contributing mechanism. We sought to determine the effects of acute exercise on endothelial-derived circulating factors proposed to reflect endothelial integrity and activation. Young, healthy men (n = 10) underwent 30-min moderate continuous (MOD) and high-intensity interval (HII) cycling exercise bouts. Venous blood samples were taken immediately before and after exercise for quantification of circulating endothelial cells (CECs), circulating angiogenic cells (CACs), apoptotic and activated endothelial microvesicles (EMVs), thrombomodulin (TM), von Willebrand factor (vWF), syndecan-1, and circulating microRNAs (ci-miRs) 126-3p and 126-5p. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery before, 10 min after, and 60 min after exercise. Numbers of CECs and EMVs were unchanged by either exercise bout (P > 0.05). Numbers of all measured CAC subtypes decreased in response to MOD (21%-34%, P < 0.05), whereas only CD31+/34+/45dim/- CACs decreased following HII (21%, P < 0.05). TM and syndecan-1 increased with both exercise intensities (both ~20%, P < 0.05). HII, but not MOD, increased vWF (88%, P < 0.001), ci-miR-126-3p (92%, P = 0.009) and ci-miR-126-5p (110%, P = 0.01). The changes in several circulating factors correlated with changes in FMD following either one or both intensities. Changes in circulating factors do not support the concept of exercise-induced endothelial cell denudation, apoptosis, or activation, though slight disruption of endothelial glycocalyx and membrane integrity may occur. A related loss of mechanotransduction along with mechanisms underlying endothelial activation and ci-miR-126 secretion may relate to changes in endothelial function.NEW & NOTEWORTHY Using circulating endothelial-derived factors, we show that endothelial denudation, apoptosis, and activation do not appear to increase, whereas disrupted endothelial glycocalyx and membrane integrity may occur during both high-intensity interval and moderate intensity cycling. Increases in factors nonspecific to endothelial damage, including von Willebrand factor and microRNA-126, occurred only after high-intensity interval exercise. These results shed light on the hypothesis that disrupted endothelial integrity contributes to the endothelial function response to exercise.

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women.

Postmenopausal African American women are at elevated risk for metabolic syndrome (MetS), which predisposes them to cardiovascular disease and other chronic diseases. Circulating microRNAs (ci-miR) are potential mediators of cardiometabolic diseases also impacted by cardiorespiratory fitness (CRF) level. Using real-time quantitative PCR, we compared the expression of vascular-related ci-miRs (miR-21-5p, miR-92a-3p, miR-126-5p, miR-146a-5p, miR-150-5p, miR-221-3p) in sedentary, overweight/obese, postmenopausal African American women based on 1) presence (n = 31) or absence (n = 42) of MetS and 2) CRF level (VO2peak ) (Very Low < 18.0 mL·kg-1 ·min-1 [n = 31], Low = 18.0-22.0 mL·kg-1 ·min-1 [n = 24], or Moderate >22.0 mL·kg-1 ·min-1 [n = 18]). Endothelial migration rate in response to subjects' serum was assessed to determine the effect of circulating blood-borne factors on endothelial repair. Ci-miR-21-5p was the only ci-miR that differed between women with MetS compared to those without MetS (0.93 ± 0.43 vs. 1.28 ± 0.71, P = 0.03). There were borderline significant differences (P = 0.06-0.09) in ci-miR-21-5p, 126-5p, and 221-3p levels between the CRF groups, and these three ci-miRs correlated with VO2peak (r = -0.25 to -0.28, P < 0.05). Endothelial migration rate was impaired in response to serum from women with MetS compared to those without after 16-24 h. Serum from women with Moderate CRF induced greater endothelial migration than the Very Low and Low CRF groups after 4 and 16-24 h, that was also not different from a young, healthy reference group. Ci-miR-21-5p is lower in postmenopausal African American women with MetS, while ci-miRs-21-5p, 126-5p, and 221-3p are associated with CRF. Factors which impair endothelial cell migration rate are present in serum of women with MetS, though having Moderate CRF may be protective.

Exercise and Cardiovascular Progenitor Cells.

Autologous stem/progenitor cell-based methods to restore blood flow and function to ischemic tissues are clinically appealing for the substantial proportion of the population with cardiovascular diseases. Early preclinical and case studies established the therapeutic potential of autologous cell therapies for neovascularization in ischemic tissues. However, trials over the past ∼15 years reveal the benefits of such therapies to be much smaller than originally estimated and a definitive clinical benefit is yet to be established. Recently, there has been an emphasis on improving the number and function of cells [herein generally referred to as circulating angiogenic cells (CACs)] used for autologous cell therapies. CACs include of several subsets of circulating cells, including endothelial progenitor cells, with proangiogenic potential that is largely exerted through paracrine functions. As exercise is known to improve CV outcomes such as angiogenesis and endothelial function, much attention is being given to exercise to improve the number and function of CACs. Accordingly, there is a growing body of evidence that acute, short-term, and chronic exercise have beneficial effects on the number and function of different subsets of CACs. In particular, recent studies show that aerobic exercise training can increase the number of CACs in circulation and enhance the function of isolated CACs as assessed in ex vivo assays. This review summarizes the roles of different subsets of CACs and the effects of acute and chronic exercise on CAC number and function, with a focus on the number and paracrine function of circulating CD34+ cells, CD31+ cells, and CD62E+ cells. © 2019 American Physiological Society. Compr Physiol 9:767-797, 2019.

The historical context and scientific legacy of John O. Holloszy.

John O. Holloszy, as perhaps the world's preeminent exercise biochemist/physiologist, published >400 papers over his 50+ year career, and they have been cited >41,000 times. In 1965 Holloszy showed for the first time that exercise training in rodents resulted in a doubling of skeletal muscle mitochondria, ushering in a very active era of skeletal muscle plasticity research. He subsequently went on to describe the consequences of and the mechanisms underlying these adaptations. Holloszy was first to show that muscle contractions increase muscle glucose transport independent of insulin, and he studied the mechanisms underlying this response throughout his career. He published important papers assessing the impact of training on glucose and insulin metabolism in healthy and diseased humans. Holloszy was at the forefront of rodent studies of caloric restriction and longevity in the 1980s, following these studies with important cross-sectional and longitudinal caloric restriction studies in humans. Holloszy was influential in the discipline of cardiovascular physiology, showing that older healthy and diseased populations could still elicit beneficial cardiovascular adaptations with exercise training. Holloszy and his group made important contributions to exercise physiology on the effects of training on numerous metabolic, hormonal, and cardiovascular adaptations. Holloszy's outstanding productivity was made possible by his mentoring of ~100 postdoctoral fellows and substantial NIH grant funding over his entire career. Many of these fellows have also played critical roles in the exercise physiology/biochemistry discipline. Thus it is clear that exercise biochemistry and physiology will be influenced by John Holloszy for numerous years to come.

Effects of regular endurance exercise on GlycA: Combined analysis of 14 exercise interventions.

BACKGROUND AND AIMS: GlycA is a relatively new biomarker for inflammation as well as cardiometabolic disease risk. However, the effect of exercise on GlycA is largely unknown. Therefore, the purpose of this study was to examine the effects of regular exercise on the inflammatory marker GlycA across seven studies and 14 exercise interventions. METHODS: Nuclear magnetic resonance spectroscopy, specifically signal amplitudes originating from the N-acetyl methyl group protons of the N-acetylglucosamine residues on the glycan branches of glycoproteins, was used to quantify GlycA concentrations. GlycA was measured before and after completion of an exercise intervention in 1568 individuals across seven studies and 14 exercise interventions. Random effects inverse variance weighting models were used to pool effects across interventions. RESULTS: Combined analysis of unadjusted data showed that regular exercise significantly (p = 2 × 10-6) reduced plasma GlycA (-8.26 ±â€¯1.8 µmol/L). This reduction remained significant (-9.12 ±â€¯1.9 µmol/L, p = 1.22 × 10-6) following adjustment for age, sex, race, baseline BMI, and baseline GlycA. Changes in GlycA were correlated with changes in traditional inflammatory markers, C-reactive protein, interleukin-6, and fibrinogen, however, these correlations were relatively weak (range r: 0.21-0.38, p < 0.0001). CONCLUSIONS: Regular exercise significantly reduced plasma GlycA across 14 different exercise interventions despite differences in exercise programs and study populations. The current study provides a greater understanding of the use of exercise as a potential therapy for the reduction of systemic inflammation. Further research is needed to understand the mechanisms behind the exercise-related reductions in GlycA.

Effect of exercise on metabolic syndrome in black women by family history and predicted risk of breast cancer: The FIERCE Study.

BACKGROUND: This study examined the effects of supervised and home-based exercise interventions on changes in metabolic syndrome (MetS) according to breast cancer risk (high vs low) in black women enrolled in the Focused Intervention on Exercise to Reduce Cancer (FIERCE) trial. METHODS: Postmenopausal, obese, metabolically unhealthy black women, 45 to 65 years old, were randomized to supervised aerobic exercise (73 women), home-based walking-based exercise (69 women), or a control arm (71 women). Participants in the exercise arms underwent a 6-month intervention with study assessments conducted at the baseline and 6 months. The primary outcome measure was MetS (fasting glucose, waist circumference, blood pressure, serum triglycerides, and high-density lipoprotein [HDL]). The intervention effects on MetS, stratified by breast cancer risk as measured by the family history of breast cancer and model-based projected breast cancer risk, were examined with intent-to-treat analyses using generalized estimating equation models. RESULTS: Among women with a family history of breast cancer, the exercise arms had lower mean MetS z scores, which suggested an improvement in the metabolic profile, than controls at 6 months (controls, + 0.55; home-based arm, -0.97, P < .01; supervised arm, -0.89, P < .01). Stratified analyses by projected breast cancer risk suggested similar but statistically nonsignificant findings, with those at high risk having more favorable changes in the MetS z score in the exercise arms versus the control arm. These changes were primarily attributable to changes in blood pressure, triglycerides, and HDL. CONCLUSIONS: Short-term aerobic activity regimens may improve the metabolic profile and thereby reduce breast cancer risk in obese, metabolically unhealthy black women at high risk for cancer. © 2018 American Cancer Society.