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•Is high-altitude myocardial injury (HAMI) as observed in rats relevant for humans?•Severe cardiac pathology considering minor changes in blood oxygenation.•Surprising convergent ...benefits of pro- and anti-ferroptosis agents for HAMI.
Regular exercise exerts a number of beneficial systemic effects and is associated with better health and performance as well as with reduced vulnerability and mortality from many diseases. While the ...working muscles are immediately affected by physical and biochemical consequences of physical activity, it is less well understood, how exercise-stimuli can lead to benefits in distant tissues and organs. Various modes of inter-tissue communication are likely involved and include physical-activity related systemic temperature and metabolic changes but also circulating signaling molecules, sometimes refered to as “exerkines”.
We are particularly interested in a subgroup of these signaling molecules, namely those that are induced by mitochondrial stress and communicate such stimuli to remote organs, effecting mitochondrial changes there. This group of molecules is termed mitokines and includes peptides that are expressed in the nucleus, such as FGF21 and GDF15, and mitochondria-derived peptides, notably humanin. Mitokines are likely important contributors to beneficial exercise effects to organs such as the brain, heart or lung and therefore are involved in the well-acknowledged physical activity-induced protection from neurological, cardio-vascular diseases and pulmonary diseases.
The activation of mitokine-signaling requires mitochondrial stress, which in healthy organisms is usually met with the induction of adaptive mechanisms that bolster cellular resilience, for example by an improving the efficiency of anti-oxidant and anti-inflammatory defense mechanisms. Such adaptations are thought to be protective factors in many diseases from which regular exercise can protect. Mitochondrial stress, however, can also be detrimental under certain conditions and especially, if the stress exceeds the adaptive capacities of the system (cell, tissue, organ or organism) or, if the resilience of the system is compromised, for example due to disease, fatigue or insufficient regeneration time from previous stressors. The concept of such bi-phasic responses is termed hormesis and means that mild stress is met by beneficial adaptations and protections but severe stress has long-term detrimental consequences.
The aim of this contribution is to present the evidence that mitochondrial stress due to exercising skeletal muscle leads to the release of mitokines, which in turn modulate mitochondrial quality control, dynamics, antioxidative capacities and respirational activity in a selection of target organs (with a focus on brain and lung). According to the hormetic principle, exercise improves the health of these organs. However, in some cases, mitochondrial communication may be involved in adverse effects of exercise, which will be discussed using the example of heart-kidney mitochondrial crosstalk.
Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low ...barometric pressure and partial pressure of O
, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.
ObjectivesThe effects of altitude residence on ageing, longevity and mortality are poorly understood. While adaptations to chronic exposure to altitude may exert beneficial effects on cardiovascular ...risk factors and some types of cancer, an elevated risk to die from chronic respiratory diseases has been reported. Moreover, high-altitude residence may be correlated with increased depression and suicide rates. The present study tested the hypothesis that living at moderate altitudes (up to 2000 m) is associated with reduced mortality from all causes.Setting and participantsWe used a dataset comprising all deaths (n=467 834) across 10 years of a country (Austria) characterised by varying levels of altitudes up to 2000 m.Main outcome measuresTotal number of deaths, age-standardised mortality rates (ASMRs) per 100 000 population, cause-specific ASMRs.ResultsASMRs for residents living in higher (>1000 m) versus lower (<251 m) altitude regions (with agriculture employment below 3%) were 485.8 versus 597.0 (rate ratio and 95% CI 0.81 (0.72 to 0.92); p<0.001) for men and 284.6 versus 365.5 (0.78; 0.66 to 0.91); p=0.002) for women. Higher levels of agriculture employment did not influence mortality rates. Diseases of the circulatory system and cancers were main contributors to lower mortality rates at higher altitude. Residence at higher altitude did not negatively affect mortality rates from any other diseases. We highlight gender effects and—beside environmental factors—also discuss socioeconomic factors that may be responsible for conflicting results with data from other populations.ConclusionsLiving at moderate altitude (1000–2000 m) elicits beneficial effects on all-cause mortality for both sexes, primarily due to lower ASMRs from circulatory diseases and cancer. The presented analysis on cause-specific ASMRs over a 10-year period among the entire population of an alpine country will contribute to a better understanding on the effects of altitude-related mortality.
Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington's disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration ...remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt cytoplasmic and nuclear inclusions in mammalian cells and primary neurons overexpressing mutant exon1 of the Htt protein. Our findings provide unique insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve the polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; the recruitment and accumulation of remodeled or dysfunctional membranous organelles, and the impairment of the protein quality control and degradation machinery. We also show that nuclear and cytoplasmic Htt inclusions exhibit distinct biochemical compositions and ultrastructural properties, suggesting different mechanisms of aggregation and toxicity.
Mitochondria are central regulators of cellular metabolism, most known for their role in energy production. They can be “enhanced” by physical activity (including exercise), which increases their ...integrity, efficiency and dynamic adaptation to stressors, in short “mitochondrial fitness”. Mitochondrial fitness is closely associated with cardiorespiratory fitness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory fitness is also an integral determinant of the antiviral host defense and vulnerability to infection.
Here, we first briefly review the role of physical activity in viral infections. We then summarize mitochondrial functions that are relevant for the antiviral immune response with a particular focus on the current Coronavirus Disease (COVID-19) pandemic and on innate immune function. Finally, the modulation of mitochondrial and cardiorespiratory fitness by physical activity, aging and the chronic diseases that represent the most common comorbidities of COVID-19 is discussed.
We conclude that a high mitochondrial - and related cardiorespiratory - fitness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mitochondrial fitness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory fitness of COVID-19 patients and the promotion of physical activity – with all its associated health benefits – as preventive measures against viral infection.
-Major COVID-19 risk factors are associated with reduced mitochondrial fitness.-SARS-coronavirus-2 infection is associated with various mitochondrial dysfunctions, also impairing the innate immune system.-Physical activity enhances immune functions, mitochondrial fitness and cardiorespiratory fitness.-Mitochondrial fitness may be an underlying molecular link between established risk factors for COVID-19.-Increasing mitochondrial and cardiorespiratory fitness, e.g. by appropriate physical activity, consequently may be a powerful preventive measure against viral infection, in particular by SARS-coronavirus-2.
High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail ...the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.
Living, working and exercising in extreme terrestrial environments are challenging tasks even for healthy humans of the modern new age. The issue is not just survival in remote environments but ...rather the achievement of optimal performance in everyday life, occupation, and sports. Various adaptive biological processes can take place to cope with the specific stressors of extreme terrestrial environments like cold, heat, and hypoxia (high altitude). This review provides an overview of the physiological and morphological aspects of adaptive responses in these environmental stressors at the level of organs, tissues, and cells. Furthermore, adjustments existing in native people living in such extreme conditions on the earth as well as acute adaptive responses in newcomers are discussed. These insights into general adaptability of humans are complemented by outcomes of specific acclimatization/acclimation studies adding important information how to cope appropriately with extreme environmental temperatures and hypoxia.
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