Brain-Periphery Interactions in Huntington's Disease: Mediators and Lifestyle Interventions.

Prominent pathological features of Huntington's disease (HD) are aggregations of mutated Huntingtin protein (mHtt) in the brain and neurodegeneration, which causes characteristic motor (such as chorea and dystonia) and non-motor symptoms. However, the numerous systemic and peripheral deficits in HD have gained increasing attention recently, since those factors likely modulate disease progression, including brain pathology. While whole-body metabolic abnormalities and organ-specific pathologies in HD have been relatively well described, the potential mediators of compromised inter-organ communication in HD have been insufficiently characterized. Therefore, we applied an exploratory literature search to identify such mediators. Unsurprisingly, dysregulation of inflammatory factors, circulating mHtt, and many other messenger molecules (hormones, lipids, RNAs) were found that suggest impaired inter-organ communication, including of the gut-brain and muscle-brain axis. Based on these findings, we aimed to assess the risks and potentials of lifestyle interventions that are thought to improve communication across these axes: dietary strategies and exercise. We conclude that appropriate lifestyle interventions have great potential to reduce symptoms and potentially modify disease progression (possibly via improving inter-organ signaling) in HD. However, impaired systemic metabolism and peripheral symptoms warrant particular care in the design of dietary and exercise programs for people with HD.

Intermittent Hypoxic Training Increases and Prolongs Exercise Benefits in Adult Untrained Women.

Alba Camacho-Cardenosa, Marta Camacho-Cardenosa, Johannes Burtscher, Pedro R. Olivares, Guillermo Olcina, and Javier Brazo-Sayavera. Intermittent hypoxic training increases and prolongs exercise benefits in adult untrained women. High Alt Med Biol. 00:00-00, 2024. Background: Exercising in hypoxia may confer multiple health benefits, but the evidence for specific benefits is scarce. Methods: We investigated effects of intermittent hypoxic training (IHT) on the quality of life and functional fitness of healthy adult women, in a double-blind, randomized, placebo-controlled study. Subjects performed 36 sessions of IHT (experimental group, n = 41; fraction of inspired oxygen [FIO2]: 0.17) or the same training in normoxia (control group, n = 41; FIO2: 0.21). Health-related quality of life, fitness tests, and hemoglobin levels were assessed before (T1), directly after (T2), and 4 weeks after (T3) cessation. Results: At T2, upper body strength (+14.96%), lower body strength (+26.20%), and agility (-4.94%) increased significantly in the experimental group compared to baseline but not in controls. The experimental group improved lower body strength more (by 9.85%) than controls at T2 and performed significantly better in walking (by 2.92%) and upper body strength testing (by 16.03%), and agility (by 4.54%) at T3. Perceived general health and vitality was significantly greater in the experimental group at T2 and T3 compared with T1. None of these improvements were observed in the control group. Conclusions: IHT is a promising strategy to induce long-lasting fitness benefits in healthy adult women.

Hypoxia Sensing and Responses in Parkinson's Disease.

Parkinson's disease (PD) is associated with various deficits in sensing and responding to reductions in oxygen availability (hypoxia). Here we summarize the evidence pointing to a central role of hypoxia in PD, discuss the relation of hypoxia and oxygen dependence with pathological hallmarks of PD, including mitochondrial dysfunction, dopaminergic vulnerability, and alpha-synuclein-related pathology, and highlight the link with cellular and systemic oxygen sensing. We describe cases suggesting that hypoxia may trigger Parkinsonian symptoms but also emphasize that the endogenous systems that protect from hypoxia can be harnessed to protect from PD. Finally, we provide examples of preclinical and clinical research substantiating this potential.

Women at Altitude: Sex-Related Physiological Responses to Exercise in Hypoxia.

Sex differences in physiological responses to various stressors, including exercise, have been well documented. However, the specific impact of these differences on exposure to hypoxia, both at rest and during exercise, has remained underexplored. Many studies on the physiological responses to hypoxia have either excluded women or included only a limited number without analyzing sex-related differences. To address this gap, this comprehensive review conducted an extensive literature search to examine changes in physiological functions related to oxygen transport and consumption in hypoxic conditions. The review encompasses various aspects, including ventilatory responses, cardiovascular adjustments, hematological alterations, muscle metabolism shifts, and autonomic function modifications. Furthermore, it delves into the influence of sex hormones, which evolve throughout life, encompassing considerations related to the menstrual cycle and menopause. Among these physiological functions, the ventilatory response to exercise emerges as one of the most sex-sensitive factors that may modify reactions to hypoxia. While no significant sex-based differences were observed in cardiac hemodynamic changes during hypoxia, there is evidence of greater vascular reactivity in women, particularly at rest or when combined with exercise. Consequently, a diffusive mechanism appears to be implicated in sex-related variations in responses to hypoxia. Despite well-established sex disparities in hematological parameters, both acute and chronic hematological responses to hypoxia do not seem to differ significantly between sexes. However, it is important to note that these responses are sensitive to fluctuations in sex hormones, and further investigation is needed to elucidate the impact of the menstrual cycle and menopause on physiological responses to hypoxia.

Exercise and gait/movement analyses in treatment and diagnosis of Parkinson's Disease.

Cardinal motor symptoms in Parkinson's disease (PD) include bradykinesia, rest tremor and/or rigidity. This symptomatology can additionally encompass abnormal gait, balance and postural patterns at advanced stages of the disease. Besides pharmacological and surgical therapies, physical exercise represents an important strategy for the management of these advanced impairments. Traditionally, diagnosis and classification of such abnormalities have relied on partially subjective evaluations performed by neurologists during short and temporally scattered hospital appointments. Emerging sports medical methods, including wearable sensor-based movement assessment and computational-statistical analysis, are paving the way for more objective and systematic diagnoses in everyday life conditions. These approaches hold promise to facilitate customizing clinical trials to specific PD groups, as well as personalizing neuromodulation therapies and exercise prescriptions for each individual, remotely and regularly, according to disease progression or specific motor symptoms. We aim to summarize exercise benefits for PD with a specific emphasis on gait and balance deficits, and to provide an overview of recent advances in movement analysis approaches, notably from the sports science community, with value for diagnosis and prognosis. Although such techniques are becoming increasingly available, their standardization and optimization for clinical purposes is critically missing, especially in their translation to complex neurodegenerative disorders such as PD. We highlight the importance of integrating state-of-the-art gait and movement analysis approaches, in combination with other motor, electrophysiological or neural biomarkers, to improve the understanding of the diversity of PD phenotypes, their response to therapies and the dynamics of their disease progression.

The link between impaired oxygen supply and cognitive decline in peripheral artery disease.

Although peripheral artery disease (PAD) primarily affects large arteries outside the brain, PAD is also associated with elevated cerebral vulnerabilities, including greater risks for brain injury (such as stroke), cognitive decline and dementia. In the present review, we aim to evaluate recent literature and extract information on potential mechanisms linking PAD and consequences on the brain. Furthermore, we suggest novel therapeutic avenues to mitigate cognitive decline and reduce risk of brain injury in patients with PAD. Various interventions, notably exercise, directly or indirectly improve systemic blood flow and oxygen supply and are effective strategies in patients with PAD or cognitive decline. Moreover, triggering protective cellular and systemic mechanisms by modulating inspired oxygen concentrations are emerging as potential novel treatment strategies. While several genetic and pharmacological approaches to modulate adaptations to hypoxia showed promising results in preclinical models of PAD, no clear benefits have yet been clinically demonstrated. We argue that genetic/pharmacological regulation of the involved adaptive systems remains challenging but that therapeutic variation of inspired oxygen levels (e.g., hypoxia conditioning) are promising future interventions to mitigate associated cognitive decline in patients with PAD.

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases.

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect the diverse forms of aSyn may lead to inaccurate estimations of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterized an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn, and that recognizes all monomeric, oligomeric, and fibrillar aSyn conformations. Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneous forms of aSyn pathology, rich in Serine 129 phosphorylation, Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered both to neurons and glia. In addition, we show that aSyn can become hyperphosphorylated during processes of aggregation and inclusion maturation in neuronal and animal models of aSyn seeding and spreading. The validation pipeline we describe for these antibodies paves the way for systematic investigations into aSyn pathological diversity in the human brain, peripheral tissues, as well as in cellular and animal models of synucleinopathies.

Recommendations for Women in Mountain Sports and Hypoxia Training/Conditioning.

The (patho-)physiological responses to hypoxia are highly heterogeneous between individuals. In this review, we focused on the roles of sex differences, which emerge as important factors in the regulation of the body's reaction to hypoxia. Several aspects should be considered for future research on hypoxia-related sex differences, particularly altitude training and clinical applications of hypoxia, as these will affect the selection of the optimal dose regarding safety and efficiency. There are several implications, but there are no practical recommendations if/how women should behave differently from men to optimise the benefits or minimise the risks of these hypoxia-related practices. Here, we evaluate the scarce scientific evidence of distinct (patho)physiological responses and adaptations to high altitude/hypoxia, biomechanical/anatomical differences in uphill/downhill locomotion, which is highly relevant for exercising in mountainous environments, and potentially differential effects of altitude training in women. Based on these factors, we derive sex-specific recommendations for mountain sports and intermittent hypoxia conditioning: (1) Although higher vulnerabilities of women to acute mountain sickness have not been unambiguously shown, sex-dependent physiological reactions to hypoxia may contribute to an increased acute mountain sickness vulnerability in some women. Adequate acclimatisation, slow ascent speed and/or preventive medication (e.g. acetazolamide) are solutions. (2) Targeted training of the respiratory musculature could be a valuable preparation for altitude training in women. (3) Sex hormones influence hypoxia responses and hormonal-cycle and/or menstrual-cycle phases therefore may be factors in acclimatisation to altitude and efficiency of altitude training. As many of the recommendations or observations of the present work remain partly speculative, we join previous calls for further quality research on female athletes in sports to be extended to the field of altitude and hypoxia.

Mechanisms underlying the health benefits of intermittent hypoxia conditioning.

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non-pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well-characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia-activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure.

The V˙O2max Legacy of Hill and Lupton (1923)-100 Years On.

PURPOSE: One hundred years ago, Hill and Lupton introduced the concept of maximal oxygen uptake (V˙O2max), which is regarded as "the principal progenitor of sports physiology." We provide a succinct overview of the evolvement of research on V˙O2max, from Hill and Lupton's initial findings to current debates on limiting factors for V˙O2max and the associated role of convective and diffusive components. Furthermore, we update the current use of V˙O2max in elite endurance sport and clinical settings. Practical Applications and Conclusions: V˙O2max is a healthy and active centenarian that remains a very important measure in elite endurance sports and additionally contributes as an important vital sign of cardiovascular function and fitness in clinical settings. Over the past 100 years, guidelines for the test protocols and exhaustion criteria, as well as the understanding of limiting factors for V˙O2max, have improved dramatically. Presently, possibilities of accurate and noninvasive determination of the convective versus diffusive components of V˙O2max by wearable sensors represent an important future application. V˙O2max is not only an indicator of cardiorespiratory function, fitness, and endurance performance but also represents an important biomarker of cardiovascular function and health to be included in routine assessment in clinical practice.

Immune consequences of exercise in hypoxia: A narrative review.

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type, dose (frequency/duration, intensity), and individual characteristics. Similarly, reduced availability of ambient oxygen (hypoxia) modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia. How combined exercise and hypoxia (e.g., high-altitude training) sculpts immune responses is not well understood, although such combinations are becoming increasingly popular. Therefore, in this paper, we summarize the impact on immune responses of exercise and of hypoxia, both independently and together, with a focus on specialized cells in the innate and adaptive immune system. We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia, then we discuss how they may be modulated by nutritional strategies. Mitochondrial, antioxidant, and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism, resilience, and overall immune functions by regulating the survival, differentiation, activation, and migration of immune cells. This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions. Appropriate acclimatization, training, and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.

Intermittent hypoxia: a call for harmonization in terminology.

Mild intermittent hypoxia may be a potent novel strategy to improve cardiovascular function, motor and cognitive function, and altitude acclimatization. However, there is still a stigma surrounding the field of intermittent hypoxia (IH). Major contributors to this stigma may be due to the overlapping terminology, heterogeneous methodological approaches, and an almost dogmatic focus on different mechanistic underpinnings in different fields of research. Many clinicians and investigators explore the pathophysiological outcomes following long-term exposure to IH in an attempt to improve our understanding of sleep apnea (SA) and develop new treatment plans. However, others use IH as a tool to improve physiological outcomes such as blood pressure, motor function, and altitude acclimatization. Unfortunately, studies investigating the pathophysiology of SA or the potential benefit of IH use similar, unstandardized terminologies facilitating a confusion surrounding IH protocols and the intentions of various studies. In this perspective paper, we aim to highlight IH terminology-related issues with the aim of spurring harmonization of the terminology used in the field of IH research to account for distinct outcomes of hypoxia exposure depending on protocol and individuum.

Environmental and behavioral regulation of HIF-mitochondria crosstalk.

Reduced oxygen availability (hypoxia) can lead to cell and organ damage. Therefore, aerobic species depend on efficient mechanisms to counteract detrimental consequences of hypoxia. Hypoxia inducible factors (HIFs) and mitochondria are integral components of the cellular response to hypoxia and coordinate both distinct and highly intertwined adaptations. This leads to reduced dependence on oxygen, improved oxygen supply, maintained energy provision by metabolic remodeling and tapping into alternative pathways and increased resilience to hypoxic injuries. On one hand, many pathologies are associated with hypoxia and hypoxia can drive disease progression, for example in many cancer and neurological diseases. But on the other hand, controlled induction of hypoxia responses via HIFs and mitochondria can elicit profound health benefits and increase resilience. To tackle pathological hypoxia conditions or to apply health-promoting hypoxia exposures efficiently, cellular and systemic responses to hypoxia need to be well understood. Here we first summarize the well-established link between HIFs and mitochondria in orchestrating hypoxia-induced adaptations and then outline major environmental and behavioral modulators of their interaction that remain poorly understood.