Cross, Troy James

During severe exercise, expiratory and inspiratory muscle fatigue develops by ∼50% of the tolerable exercise duration. The magnitude of expiratory and inspiratory muscle fatigue increases progressively toward exercise intolerance but is not different between muscle groups; this is despite the expiratory muscles being less fatigue-resistant. Inspecting esophageal and gastric twitches via cervical stimulation, we speculate that the progressive magnitude of exercise-induced inspiratory muscle fatigue is a function of recruitment and fatigue of the accessory inspiratory muscles.

Respiratory muscle fatigue could occur following involuntary breathing movements during maximal breath-holds. We measured respiratory muscle strength pre and post three preparatory and maximal breath-holds. We found significant reductions in diaphragm strength and total inspiratory and expiratory strength in some, but not all, divers. Divers that had respiratory muscle fatigue had a lower pseudo O 2 delivery (HR × [Formula: see text]) during the struggle phase. This suggests that reduced oxygen delivery may contribute to respiratory muscle fatigue during a breath-hold.

Exercise-induced respiratory muscle fatigue contributes to limiting exercise tolerance. Accordingly, better understanding the exercise conditions under which respiratory muscle fatigue occurs is warranted. Although heavy-intensity as well as short- and long-duration severe-intensity exercise performed to intolerance elicit diaphragm and expiratory muscle fatigue, we find, for the first time, that the relationship between exercise intensity, exercise duration, and the magnitude of exercise-induced fatigue is different for the diaphragm compared with the expiratory muscles.

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β 1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures.

The measurement of the work of breathing (Wb) during exercise provides us with deep insights into respiratory (patho)physiology, and sheds light on the putative factors which lead to respiratory muscle fatigue. There are 4 popular methods available to determine the Wb. Our study demonstrates that no two of these methods produce identical values of Wb during exercise. This paper also discusses the practical and theoretical limitations of each method.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol . 22:249–262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO 2 ) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (F I O 2 : 0.125) and normoxia (F I O 2 : 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO 2 was systematically higher after drug (peak exercise SaO 2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO 2 diff) and consumption (VO 2 ) were similar (peak exercise Ca-vO 2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO 2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO 2 was systematically higher after drug, whereas peak VO 2 was reduced (peak exercise SaO 2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO 2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO 2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

There are growing concerns that the COVID-19 pandemic has facilitated a sedentary shift in our physical activity habits. A reduction in physical activity during the pandemic may be secondary to restrictive policies implemented at the government-level, typically those policies which limit interpersonal contact; for example, physical/social distancing. It is without question that social distancing is a necessary measure to mitigate community transmission of the novel virus; however, these policies often limit the public’s opportunities to engage in physical activity. The strictest enforcement of social distancing occurs during an authority-mandated ‘lockdown’ (also known as a ‘shelter-in-place’ or ‘stay-at-home’ order). This Viewpoint focuses on the current evidence demonstrating that physical activity declines during a COVID-19 ‘lockdown’. We highlight the point that most of the available evidence stems from investigations using non-validated, self-reported measures of physical activity and discuss the caveats therewith. This Viewpoint explores whether current evidence reflects an ‘actual’ or rather a ‘perceived’ reduction in physical activity, and raises the question of whether this distinction matters in the end.

The modified Campbell diagram provides one of the most comprehensive assessments of the work of breathing (Wb) during exercise, wherein the resistive and elastic work of inspiration and expiration are quantified. Importantly, a necessary step in constructing the modified Campbell diagram is to obtain a value for chest wall compliance (CCW). To date, it remains unknown whether estimating or directly measuring CCW impacts the Wb, as determined by the modified Campbell diagram. Therefore, the purpose of this study was to evaluate whether the components of the Wb differ when the modified Campbell diagram is constructed using an estimated versus measured value of CCW. Forty-two participants ( n = 26 men, 16 women) performed graded exercise to volitional exhaustion on a cycle ergometer. CCW was measured directly at rest via quasistatic relaxation. Estimated values of CCW were taken from prior literature. The measured value of CCW was greater than that obtained via estimation (214 ± 52 mL/cmH2O vs. 189 ± 18 mL/cmH2O; P < 0.05). At modest-to-high minute ventilations (i.e., 50–200 L/min), the inspiratory elastic Wb was greater and expiratory resistive Wb was lower, when modified Campbell diagrams were constructed using estimated compared with measured values of CCW ( P = 0.001). These differences were however small and never exceeded ±5%. Thus, although our findings demonstrate that estimating CCW has a measurable impact on the determination of the Wb, its effect appears relatively small within a cohort of healthy adults during graded exercise.

In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.