Feature Papers in Human Physiology–2nd Edition

Recommendations for endurance exercise prescription are often based on percentages of heart rate (HR) or the volume of oxygen consumption ($\dot{\mathrm{V}}$O₂) maximum or reserve that is extrapolated to a power output (P) or velocity. Previous work has demonstrated dissociations of the expected responses to exercise anchored to the critical heart rate (CHR) compared with the P associated with CHR. However, it is unclear if similar dissociations due to reductions in P to maintain the designated intensity would be present during exercise anchored to the $\dot{\mathrm{V}}$O₂ associated with CHR ($\dot{\mathrm{V}}$O₂CHR). The purpose of this study was to examine the patterns in physiological ($\dot{\mathrm{V}}$O₂, HR, P, respiration rate [RR], muscle oxygen saturation [%SmO₂]), neuromuscular (electromyographic and mechanomyographic amplitude [EMG AMP, MMG AMP], mean power frequency [EMG MPF, MMG MPF]), and perceptual (rating of perceived exertion [RPE]) responses during exercise at $\dot{\mathrm{V}}$O₂CHR ($\dot{\mathrm{V}}$O₂-clamp). On separate days, ten participants (age: 25 ± 4 yr) performed a graded exercise test and four constant P trials at 85–100% of peak P (PP) to derive CHR and $\dot{\mathrm{V}}$O₂CHR. Responses were recorded during a trial to exhaustion at $\dot{\mathrm{V}}$O₂CHR (32.86 ± 7.12 mL·kg⁻¹·min⁻¹; T_Lim = 31.31 ± 21.37 min) and normalized in 10% intervals of T_Lim to their respective values at PP. The one-way repeated-measures ANOVA with post hoc, Bonferroni-corrected, pairwise comparisons indicated differences (p < 0.001) from baseline for HR (mean ± SD %change = 8 ± 3%), RR (43 ± 38%), P (−15 ± 5%), EMG MPF (10 ± 8%), and RPE (65 ± 38%), but no differences (p = 0.077–0.955) for %SmO₂ (−17 ± 53%), EMG AMP (−3 ± 16%), MMG AMP (40 ± 61%), and MMG MPF (1 ± 7%). The loss in performance observed during $\dot{\mathrm{V}}$O₂-Clamp exercise may provide a quantification of the inefficiency associated with the $\dot{\mathrm{V}}$O₂ slow component phenomenon. The neuromuscular responses suggested constant muscle excitation despite the reductions in P, but the metabolic and perceptual responses suggested a combination of feedforward and feedback mechanisms regulating T_Lim. Future studies should further examine responses to the $\dot{\mathrm{V}}$O₂-Clamp exercise at a uniform threshold. Full article

The physiological mechanisms for releasing and resolving gravitational ischemia in the brain, and their susceptibility to malfunction, may play an important role in a variety of neurological illnesses. An astronaut on a space walk in a micro-gravity environment may be susceptible to neuro-ocular symptoms associated with unopposed gravity-resistance mechanisms for partially preventing gravitational ischemia in the brain, and for attenuating its impact—mechanisms which may be required for normal brain physiology on Earth. Astronauts on the International Space Station typically breathe a mixture of gasses similar in composition to what they breathed on Earth, following the 1967 death of three astronauts, including Ed White, by fire on the Apollo 1 spacecraft, which was carrying 100% oxygen. For the last decade, astronauts have been studied extensively by flight physicians regarding the commonly experienced symptoms of VIIP, or ‘visual impairment and intracranial pressure’ syndrome. In this paper, we compare VIIP syndrome to the neuro-ocular and Parkinson’s-like symptoms which occurred during and after the 1918–1919 influenza pandemic. The common denominator may be gravitational ischemia in the brain, and the mirror-imaging failed mechanisms for its release (in influenza) versus unopposed gravity-resistance mechanisms (in astronauts). Some research has suggested that astronauts may benefit from breathing oxygen concentrations somewhat higher than 20%, and under slightly elevated pressure. These may possibly prevent maladaptive mechanisms leading to Alzheimer’s- or Parkinson’s-like illness by compensating for impaired mechanisms for releasing and resolving gravitational ischemia in the brain. Full article

The purpose of the present study was to investigate the effect of ischemic preconditioning (IPC) on the recovery of exercise performance following maximal, incremental exercise. A total of 13 healthy males volunteered to participate, undertaking three experimental trials involving a constant work-rate bout of severe intensity exercise undertaken to the limit of tolerance that was preceded by a 40-min recovery period consequent to a maximal, incremental exercise test. During the recovery period, participants underwent IPC at 220 mmHg, sham IPC (SHAM; 20 mmHg), and passive rest (CON). Exercise tolerance time was higher following IPC as compared to SHAM and CON {199 ± 36 (CON) vs. 203 ± 35 (SHAM) vs. 219 ± 34 (IPC), p = 0.03}. This effect was accompanied by a tendency toward an augmented increase in blood lactate from rest to exercise in IPC compared to SHAM and CON (p = 0.08). There was no effect of IPC on oxygen uptake kinetics or muscle oxygenation as indicated via near-infrared spectroscopy. IPC may therefore have the capacity to augment recovery from prior maximal exercise, but this does not appear to be due to enhancements to oxygen uptake kinetics or muscle oxygenation. Full article

Herein, we determined if a multi-ingredient supplement (NAD3; 312 mg of combined Wasabia japonica extract, theacrine, and copper (I)niacin chelate) versus a placebo (CTL) affected peripheral blood mononuclear (PMBC) transcriptomic, DNA methylation, and sirtuin activity profiles in middle-aged adults after 12 weeks of supplementation. Several mRNAs demonstrated interactions (n = 148 at ±1.5-fold change, p < 0.01), and more stringent filtering indicated that 25 mRNAs were upregulated and 29 were downregulated in the NAD3 versus CTL group. Bioinformatics on these 64 mRNAs suggested that DNA conformational alterations may have been promoted with NAD3 supplementation, and this was corroborated with more CpG sites being hypermethylated (p < 0.001) in the CTL versus the NAD3 group when examining pre- to post-intervention changes (369 versus 35). PBMC SIRT activity decreased in CTL participants (p < 0.001), but not in NAD3 participants (p = 0.289), and values at 12 weeks trended higher in NAD3 participants (p = 0.057). Interestingly, the pre- to post- changes in SIRT activity values significantly correlated with changes in PBMC NAD⁺: NADH values obtained from a previous investigation in these participants (r = 0.534, p = 0.015). In conclusion, the current mRNA and DNA methylation data indirectly suggest that NAD3 supplementation may affect PBMC DNA conformation, while other direct assays suggest that NAD3 supplementation maintains SIRT activity through the potential maintenance of NAD⁺: NADH levels. However, these results are preliminary due to limited n-sizes and the study being performed in middle-aged adults. Full article

There is a gap in the current knowledge on the immediate mechanisms of cardiovascular regulation in human subjects within short-term exposure to modeled microgravity using “dry” immersion. Aim. The purpose of the study was to evaluate cardiovascular responses in young healthy subjects during a 45 min session with the help of linear and nonlinear heart rate variability and hemodynamics parameters. The research voluntarily enrolled 33 subjects (18 men, 15 women) aged 19–23 years old. Results. The study showed that systolic and diastolic blood pressure was quite stable, some time-domain parameters of heart rate variability (SDNN, RMSSD, pNN50, etc.) and the frequency-domain (TP, HF, LF, but not VLF) have significantly increased within a 45 min “dry” immersion session. Of the non-linear parameters of heart rate variability, only ApEn significantly decreased during the “dry” immersion session. Conclusion. Our results suggest that a short-term 45 min DI session provokes in young healthy subjects neurogenic autonomic reaction based on the baroreceptor reflex. This provides stable hemodynamics in these subjects along the “dry” immersion session. Full article

Background: In sporting and combat settings, optimal fluid replacement is rarely achieved, exacerbating physiological strain. It is unknown if prescribed fluid replacement following exercise in heat impacts heart rate variability (HRV). Purpose: Compare prescribed drinking (PD) and ad libitum (AL) fluid replacement on HRV following exercise in heat. Methods: Twelve participants (26 ± 5 years, VO_2max: 58.44 ± 7.05 mL·kg⁻¹·min⁻¹) completed three trials in heat (36 °C, 36% humidity) on separate days, and were placed into groups, PD or AL. Recovery was assessed ~24 h later (hydration and HRV). HRV time and frequency was measured using a 3-lead electrocardiogram. Two-way repeated measures analysis of variance measured changes in HRV pre-trial, post-trial, and follow-up between groups. Data reported: p-value, mean difference (MD). Results: Fluid consumption was greater in PD during recovery (p = 0.012, MD = 1245 mL). Both groups were euhydrated at follow-up. HRV time (p < 0.001, MD = 24.23) and frequency (p < 0.001, MD = −1.98 ms²) decreased post-trial and increased by follow-up (time, p < 0.001, MD = −32.12; frequency, p < 0.001, MD = 2.38 ms²). HRV was similar between groups (p > 0.05). Conclusions: Replacing ≥60% fluid sufficiently rehydrates and restores HRV 24 h post-exercise in heat and mild dehydration (BML ≤ 3%). Prescribed fluid consumption during recovery was ~30% greater. Additional measures of recovery sensitive to heat strain may provide a more holistic understanding of specific mechanisms of recovery. Full article

Mitochondria are crucial for cellular functioning, serving as both an intracellular energy source and a signaling organelle. Recent evidence also highlights their existence outside of cells, where they participate in cell-to-cell communication. Cardiometabolic disease (CMD) has a complex pathogenesis closely associated with mitochondrial dysregulation, inflammation, and metabolic abnormalities. This review explores the roles of circulating extracellular mitochondria (CEMI) in CMD, detailing how their various forms, whether as intact structures or within vesicles, contribute to CMD pathogenesis. We classify different forms of CEMIs and discuss their potential as biomarkers and therapeutic agents in CMDs. We also describe mitochondrial transplantation as an emerging therapy for restoring cellular function in damaged tissues. Finally, to standardize CEMI assessment, we propose the Universal CEMI Assessment Protocol (UCAP), a framework aimed at enhancing comparability and reproducibility across studies. Full article

Prediabetes, a pivotal phase in glucose metabolism between normalcy and diabetes, exerts a profound influence on the aging process and the risk of age-related diseases. This comprehensive review delves into the intricate web of blood-based biomarkers that collectively expedite senescence, marking the transition from a state of health to age-related complications. Key findings underscore the significance of diverse biomarkers, such as telomere length, p16INK4a, senescence-associated secretory phenotype (SASP) factors, DNA methylation clocks, advanced glycation end products (AGEs), inflammatory and oxidative stress markers, circulating hormones, and additional factors such as folate, B12, and osteocalcin. Not only do these biomarkers serve as indicators of senescence but they also actively fuel chronic inflammation, oxidative stress, and metabolic dysregulation, all of which contribute to accelerated aging. The implications of this understanding are profound, as prediabetes emerges as a critical period in an individual’s life, influencing various physiological systems, including the vascular and neural systems, metabolic functions, hormonal regulation, and bone health. Recognizing the profound influence of prediabetes on senescence provides a foundation for personalized intervention strategies to mitigate age-related complications and promote healthy aging. Future research directions call for a more diverse array of biomarkers, the in-depth exploration of their roles, and the development of tailored precision medicine strategies to ensure a holistic understanding and effective management of prediabetes-induced senescence and its implications for aging. This knowledge has far-reaching implications for public health and clinical practice, emphasizing the need for early detection and intervention in prediabetic individuals to enhance the quality of life in an aging population with diverse needs. Full article

When thinking of skin disease, cancer comes up almost immediately as an example. While the American Cancer Society lists 6 major cancer types, the National Institute of Arthritis and Musculoskeletal and Skin Diseases identifies 13 significant benign skin disorders, reflecting the diversity of skin conditions in dermatology. This topical review aims to provide an overview of the pathophysiology of these major skin cancers and disorders and to summarize conventional diagnostic methods and current treatment approaches. Full article

Background: Lumbar spinal stenosis causes considerable disability in everyday life; its incidence is increasing due to aging in the world population. First-line treatment is generally conservative, but rehabilitation outcome is still unclear; the aim of this systematic review was to define which domains need to be evaluated for the lumbar stenosis physiotherapy approach, further specifying if the literature suggests patient-centred or objective measures. Methods: A systematic review of the literature according to the PRISMA statement was carried out; the PICO model was used to draw research questions. RCTs about the rehabilitation of lumbar spinal stenosis conducted in the last five years were considered includible, with no difference in terms of stenosis location. The following databases were screened through specific search strings: PubMed, EBSCO, PEDro, Cochrane Database, Scopus, and Google Scholar; two independent researchers assessed results and a third opinion was requested to solve conflicts. Critical appraisal of the included studies was conducted through Pedro Jadad scores. The following data were extracted: author and year, country, sample, intervention, outcome domains, and tools. Results: From 10,069 records, three RCTs were included in the final review stage; they all showed high methodological quality. It is recommended for physiotherapists dealing with lumbar spinal stenosis to assess five main domains: disability, pain, clinical tests, mental wellbeing and kynesiophobia, and quality of life. Domains were mainly assessed through self-reported questionnaires/scales, while objective tests evaluate general lower limb movements, the active range of motion, or the muscles’ endurance. Conclusion: This five-domain evaluation model is reliable and can be practised in each rehabilitation setting (home, outpatient, and hospital); sustainability is guaranteed by the prevalent employment of self-reported tools. Future studies should evaluate the best questionnaire/scale for each domain, especially the definition of a gold standard for pain assessment in patients with lumbar stenosis as this is a challenge for the future. Full article

Psoriatic arthritis is a heterogeneous chronic autoimmune disorder characterized principally by skin lesions, arthritis, dactylitis and enthesitis. The exact etiology of the disease is yet to be discovered, with genetic predisposition alongside environmental factors being a well-known theory. In recent years, new discoveries have emphasized the role of gut microbiome in perpetuating inflammation in spondylarthritis. The exact mechanism through which dysbiosis underlies the pathophysiology of psoriatic arthritis is not defined. One of the current areas of focus in rheumatic research with new studies emerging annually is the link between microbiome and psoriatic arthritis. In this review, we synthesized the recent knowledge on intestinal microbiome and psoriatic arthritis. We screened two databases for articles, PubMed and Medline, using the following keywords: “microbiome”, “microbiota” and “psoriatic arthritis”. We described the current expertise on diversity and composition of gut microbiome in psoriatic arthritis, comparing the results with other inflammatory diseases. In the future, preventing the dysbiosis process that leads to the development of psoriatic arthritis could open the door to new therapeutic modalities. Moreover, fecal microbiota transplantation and probiotics’ benefits in modulating the gut microbiome are being intensively researched at the moment. Full article

(1) Background: The influence of estrogen on cognitive and perceptual functions is debated. Some research suggests that estrogen increases arousal, improving cognitive function, while others propose that increased arousal might reduce performance in certain tasks. This study investigates the effects of menstrual cycle phase and estrogen levels on lightness perception in cycling women and hormonal contraceptive (HC) users. (2) Methods: Sixteen women (nine with natural cycles and seven HC users) completed three sessions aligned with different menstrual cycle phases. During these sessions, participants adjusted the luminance of five test stimuli (representing blue, green, green-yellow, yellow, and red) until they matched a flickering reference white stimulus. Lightness was calculated as the ratio of the reference stimulus luminance (5 cd/m²) divided by the test luminance required to match. Estrogen levels were also determined for each participant from saliva samples collected on the morning of each session. The effects of wavelength and menstrual cycle phase on lightness perception were analyzed, followed by post hoc comparisons and correlations between lightness perception and estrogen levels for both cycling women and HC users. (3) Results: Lightness varied by menstrual phase (MCP) in cycling women and was slightly higher during the low estrogen menstrual phase compared to peri-ovulation or luteal phases. In HC users, lightness measures were equivalent across phases. For cycling women, lightness was negatively correlated with estrogen for the green and green-yellow stimuli. There were no such associations among HC users. (4) Conclusions: This report challenges the concept that high estrogen phases of the menstrual cycle always positively influence perception. Conversely, these results revealed that—at least in cycling, non-hormonal contraceptive users—lightness perception was both at a maximum during the low estrogen menstrual phase and negatively associated with estrogen levels across all tested wavelengths. Full article

Wnt signaling involves multiple pathways that contribute to organ development, cell fate, inflammation, and normal stem cell renewal and maintenance. Although the homeostasis of stem cells in the gastrointestinal (GI) tract highly depends on the Wnt signaling pathway, this regulation is impaired in cancers and in aging. Overactive (uncontrolled) Wnt signaling can induce GI epithelial cancers such as colon and gastric cancer. Overactive Wnt signaling can also contribute to the initiation and progression of gastrointestinal stromal tumor, which is the most common human sarcoma occurring in the walls of the digestive organs, mainly the stomach and small intestine. Wnt expression is positively associated not only with the progression of oncogenesis but also with resistance to chemotherapy and radiotherapy. Of note, recent reports show that decreased Wnt signaling is related to intestinal stem cell aging and that overactivated Wnt signaling leads to gastric pacemaker stem cell aging in tunica muscularis. These findings indicate that Wnt signaling has different crucial aspects of cell fate determination with age in GI tunica mucosa and muscularis. In this review, we summarize the most recent advances in our understanding of Wnt signaling pathways and their role in regulating key aspects during development, carcinogenesis, inflammation, and aging, with the ultimate goal of identifying novel therapies. Full article