The central role of mitochondrial tness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic

Redox Biology 43 (2021) 101976

 

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Review article

The central role of mitochondrial tness on antiviral defenses: An advocacy for physical activity during the COVID-19 pandemic

Johannes Burtschera,b,*, Martin Burtscherc, Gr ́egoire P. Milleta

a Institute of Sport Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland
b Department of Biomedical Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland c University of Innsbruck, A-6020, Innsbruck, Austria

ARTICLEINFO ABSTRACT

   

Keywords:

Physical activity Exercise Cardiorespiratory tness Mitochondria

COVID
Virus
Immune system

1. Introduction

Controlling the current Coronavirus Disease (COVID-19) pandemic requires the implementation of physical isolation strategies including con nement approaches that potentially lead to reduced physical ac- tivity (PA, including exercise, de ned as planned, structured, repeated and goal-directed PA [1]) levels with a variety of health consequences [2–4]. Recent calls for a more nuanced and integrated consideration of COVID-19 as a pandemic highlight its impact on a broad array of public health factors, and the importance of targeting these factors beyond “simply controlling epidemic disease or treating individual patients” [5]. This conceptualization includes the need to address also all asso- ciated comorbidities, such as hypertension, diabetes, obesity, cardio- vascular or respiratory diseases. This should be an opportunity for policy makers to advertise the importance of regular PA [6,7]. It is well established that PA levels are negatively correlated with a number of

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, ef ciency and dy- namic adaptation to stressors, in short “mitochondrial tness”. Mitochondrial tness is closely associated with cardiorespiratory tness and physical activity. Given the importance of mitochondria in immune functions, it is thus not surprising that cardiorespiratory tness is also an integral determinant of the antiviral host defense and vulnerability to infection.

Here, we rst brie y 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 tness 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 – tness should be considered as protective factors for viral infections, including COVID-19. This assumption is corroborated by reduced mito- chondrial tness in many established risk factors of COVID-19, like age, various chronic diseases or obesity. We argue for regular analysis of the cardiorespiratory tness of COVID-19 patients and the promotion of physical activity – with all its associated health bene ts – as preventive measures against viral infection.

morbidities and mortality from all causes in both the general population and athletes [8,9]. Several overviews with speci c regard to general health bene ts of maintained PA and metabolic health even in periods of con nement like during COVID-19 have recently been provided [4, 10–12]. Regular PA increases cardiorespiratory tness or aerobic power (and mitochondrial tness [13]) in a dose-dependent manner [14], which is thought to mediate the resulting health bene ts.

Here we discuss the reasons that render mitochondrial and cardio- respiratory tness a potential marker for COVID-19 vulnerability and why improving them is an important preventive measure for viral in- fections in general. In the rst section a short overview on general effects of physical exercise on immune functions is provided. We discuss, how PA modulates the function of mitochondria, integral components of eukaryotic cells that are critically involved in energy-production, oxidative stress regulation, and many other processes maintaining cellular functions. They are also importantly involved in the cellular and

* Corresponding author. University of Lausanne, Department of Biomedical Sciences, Quartier UNIL-CHUV, Rue du Bugnon 7, CH-1015, Lausanne, Switzerland.

E-mail address: johannes.burtscher@unil.ch (J. Burtscher).

https://doi.org/10.1016/j.redox.2021.101976

Received 7 January 2021; Received in revised form 6 April 2021; Accepted 12 April 2021

Available online 23 April 2021
2213-2317/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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systemic host immune response to infections. As mitochondria can be “enhanced” (i.e. “trained”) by PA, the combination of their integrity, ef ciency and dynamic adaptation to stressors, will be referred to as their “mitochondrial tness”. Most of the available knowledge on this aspect relates to skeletal muscle tissue but it is becoming increasingly apparent that PA also boosts mitochondrial functions of many other tissues [15,16,16–20]. While this review focuses primarily on the effects of PA on mitochondrial tness associated with innate immune capacities of mainly tissue-bound cells, equally important effects of exercise – and its regulatory role on metabolism – are expected on the adaptive immune system by improving mitochondrial tness and immunometabolism (de ned as the link of metabolism and immunological state) of its specialized systemic cells. We will, however, outline important de- velopments related to immunometabolism of the adaptive immune system and provide references to more specialized reviews.

We speci cally highlight the associations of cardiorespiratory tness with mitochondrial tness that could explain parts of the boosted anti- viral host response of well-trained people and possibly reduced risk for viral respiratory infections like COVID-19 on the molecular level. To this end, an overview on mitochondrial functions relevant for this topic is presented. Several considerations that render high cardiorespiratory tness a protective factor in viral infections such as in COVID-19 are outlined. Especially epidemiological risk factors, including age and chronic diseases that are characterized by reduced cardiorespiratory tness, point to this possibility. Based on these arguments, evidence on the potential of PA to augment speci c mitochondrial functions will be discussed. Despite these accepted associations, the possible role of mitochondrial and cardiorespiratory tness as potential modulators of COVID-19 infection has been rather neglected so far.

2. PA, the immune system and mitochondria

PA is known to have the capacity to boost immune functions and can strengthen the antiviral host defense, likely due to its potential to stimulate bene cial adaptations, for example to challenges imposed on the organism by exercise [21]. This capacity, however, is heavily modulated by how the PA is performed and depends on factors like volume, frequency and intensity. Regular PA of moderate intensity (approximately 3–6 metabolic equivalents, METs) enhances the ef – ciency of the immune system but vigorous-intensity PA (>6 METs) may suppress it [22–24]. Moderate PA contributes to a better distribution of leukocytes in the organism [25] and exerts anti-in ammatory effects [26]. If performed regularly, such PA improves the function and action of components of the adaptive immune system, such as tissue macro- phages, the activation of neutrophils, natural killer cells, cytotoxic T cells, immature B cells, and further also of immunoglobulins and anti-in ammatory cytokines; it may also induce the downregulation of toll-like receptor (TLR) expression on innate immune cells [27].

High cardiorespiratory tness, which can be achieved by appropriate regular PA, is generally associated with low in ammation levels [23]. An increased release of myokines and anti-in ammatory cytokines during PA is thought to be involved in the regulation of in ammation [28,29], such as IL-10, IL-37, IL-1 receptor antagonist (IL-1ra).

Accordingly, upper respiratory tract infections (URTI) are generally reduced in subjects engaging in higher amounts of PA [30] by as much as 40–50% [23]. Bene cial effects of PA directly on viral infections have also been reported in some studies. For example, higher PA levels have been shown to reduce mortality in in uenza virus [31] and cardiore- spiratory tness protected from herpes virus reactivation [32]. In mice chronic exercise reduced in ammation and protected from disease severity after in uenza infection [33].

Conversely, acute intensive exercise seems to exert adverse effects on viral infection; Davis and colleagues [34] studied the effect of exercise on pathological outcomes following respiratory tract infection with herpes simplex type 1 virus in mice. They found that exertion facilitated infection, reduced antiviral resistance of macrophages and increased

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mortality. In line with this, a large body of evidence in humans shows that prolonged bouts of high-intensity exercise correlate with elevated in ammation, reduced immune system function and increased risk of URTI, in particular after competitions [23]. Vulnerability of athletes to respiratory tract infection thus may be high [35] but certainly depends on training phase, the relative stress levels, various environmental fac- tors, is further modulated by genetic predisposition [36,37]. Paulsen and colleagues [38] discuss in detail the effects of muscle damage on in- ammatory responses in dependence of the exercise stimulus and Koelwyn and colleagues [39] vividly visualize the initial increase of in ammation via pro-in ammatory factors after muscle damage that is followed by adaptation and mitigation of in ammation.

Mitochondria are emerging as prominent factors in the regulation of the immune response [40,41] and our knowledge on mitochondrial adaptations to exercise is rapidly expanding [42]. Still, the role of mitochondrial tness in mediating the divergent outcomes of acute/- regular and moderate/intense exercise on the immune system is still poorly understood.

In an excellent recent review, Nieman and Wentz [23] locate the threshold between immunologically bene cial moderate exercise at around 60% of maximal oxygen uptake and heart rate reserve for in- tensity and at around 60 min for duration. In summary, while regular moderate activity below 60 min may increase immunosurveillance of specialized immune cells and reduce in ammation, high intensity ex- ercise may increase oxidative stress, transiently reduces immune func- tion and elevates in ammation [23].

With regard to COVID-19 – and in line with the discussed bene ts of PA – PA and high cardiorespiratory tness have been suggested to be bene cial by controlling pro-in ammatory responses and potentially by enhancing anti-viral host responses following infection [43,44]. Recently, also epidemiological support for this hypothesis has been re- ported [45]. In this study, the hospitalization of persons infected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is responsible for COVID-19, was correlated to their cardiorespiratory tness and a clear negative association was found. Similarly, muscle strength was negatively correlated with hospitalization due to COVID-19 [46]. The immune-system enhancing and anti-in ammatory effects of PA, as discussed above, are clearly highly relevant for SARS-CoV-2 host immune defense but also for subsequent cytokine re- sponses that may be inappropriate following SARS-CoV-2 infection [47] resulting in sepsis, a common cause of COVID-19 related death [48]. Sepsis, as a result of dysregulated host response to infection [49], has been directly linked to mitochondrial dysfunction and particularly to reduced energy levels in skeletal muscle biopsies of critically ill septic patients [50].

Here, we propose that mitochondria are crucial factors mediating the bene cial effects of cardiorespiratory tness on the molecular level. They enable exercise-mediated systemic improvements such as of the cardiovascular system and skeletal muscle, as well as of cellular func- tions, such as redox control and immune function, both in target tissues of infections (innate immune responses of all cells and of resident im- mune cells) and in specialized systemic immune cells in blood and lymph/lymphoid organs. Mitochondria thus regulate a number of fac- tors – beside cellular energy provision – that are important not only for cardiorespiratory tness but also for the anti-viral host defense [51,52]. Despite the recent emergence of hypotheses suggesting a protective role of mitochondrial tness [13,53] or mitochondrial dysfunction as a risk factor [54], potential drug target [55] and key factor in the pathogenesis in COVID-19 [56,57], no experimental evidence is available yet sup- porting these notions.

In order to assess the role of mitochondrial tness in viral infections, some relevant mitochondrial functions involved in the antiviral immune defenses are summarized in the following section.

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3. The intimate link of mitochondria and the anti-viral innate immune response

Mitochondria are double-membrane enclosed sub-cellular organelles best known for their role as cellular energy generators by oxidative phosphorylation in eukaryotic cells. In the course of this process mito- chondria consume a great part of the organism’s inspired oxygen. But mitochondria are also essentially involved in a wide array of other crucial processes for cellular function, comprising – beside ion homeo- stasis, redox signaling, protein and metabolite synthesis, fatty acid catabolism and the regulation of cell death and survival [58] – essential roles in the immune system and host defense to various pathogens, including viruses [52]. Mitochondria rapidly adapt to environmental stress, by changing metabolism and fuel sources, mitochondrial biogenesis, dynamics, traf cking and quality control (Fig. 1).

Upon viral infection, the functional, structural and substrate states of mitochondria change and determine the ef ciency of the innate immune response [59,60]. As part of the innate immune response cells detect pathogens via pattern recognition receptors (PRRs) including the reti- noic acid inducible gene (RIG1)-like receptors (RLR). This detection induces signaling cascades with prominent mitochondrial involvement activating interferons and pro-in ammatory cytokines with direct anti-viral activity or specialized immune cells. RLRs activate the mito- chondrial anti-viral signaling complex (MAVS), an outer mitochondrial membrane protein complex that is involved in the anti-viral host defense by inducing for example the transcription of class 1 interferons [61].

As obligate parasites viruses rely on the host cell’s molecular ma- chinery and energy [62]. Viruses therefore modulate cellular physiology and metabolism in order to use them for replication but also to evade the host cell’s immune response. The central role of mitochondria in anti-viral immune response also renders them a preferential target for viral modulation [63,64], although other organelles are also modulated [62].

Mitochondrial tness comprises numerous mitochondrial functions that work together to enable an ef cient anti-viral host response: the capacity of mitochondria to establish a mitochondrial membrane po- tential (MMP) and use oxidative phosphorylation, to regulate their numbers and quality by mitochondrial biogenesis and mitophagy, to regulate their localization and metabolic activity by traf cking and dynamics, to maintain their regular metabolic processes, ion and redox homeostasis, as well as signaling functions (including innate immune

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system signaling) and eventually cell death and survival (Fig. 1).
Some viruses evolved to bypass or counteract the mammalian viral anti-host defense and this seems to also be the case in COVID-19. COVID- 19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), an enveloped, positive sense single-stranded RNA-virus, with high genetic similarity to SARS-COV-1 the responsible virus for the SARS epidemic in 2002/2003 [65]. The main entry path of SARS-CoV-2 is via angiotensin converting enzyme 2 (ACE2) binding, which is fol- lowed by cleavage of the viral spike protein by a protease like TMPRSS2 and endocytosis-mediated import of the virus into the cell triggering the innate and adaptive immune response [66]. A dangerous complication in COVID-19 is the development of a cytokine storm, a surge in pro-in ammatory cytokines in the serum, which may result in pulmo- nary pathology, sepsis, respiratory failure or multiple organ failure [67]. Similar to what has been described for other RNA-viruses, SARS- CoV-2 RNA is predicted to localize to infected host cells’ mitochondria [68] and cause mitochondrial dysfunction [51], such as alterations in mitochondrial respiration, mitochondrial reactive oxygen species (mtROS) production or the regulation of cell death and survival. Some in vitro data support this assumption, demonstrating for example that SARS-CoV-2 binds to components of the mitochondrial membrane (TOM-70) and thereby impairs the host cell’s type I interferon response [69]. In another study only small effects of SARS-CoV-2 infection on mitochondrial DNA and MAVS gene expression in cell lines and clinical samples were reported, while nuclear genes of complex I subunits were downregulated [70]. While very few experimental data are available on the effect of mitochondrial tness on infection with SARS-CoV-2 (e.g. there may be de cits in mitochondrial respiration in peripheral blood mononuclear cells of COVID-19 patients [71]), several pieces of evi- dence suggest mitochondrial integrity to be crucial for the general anti-viral host defense [51,72]. In the following sections these argu- ments are discussed for the individual components of mitochondrial

tness.

3.1. Mitochondrial membrane potential

The mitochondrial membrane potential (MMP) denotes the differ- ence of electrical potential across the inner mitochondrial membrane and together with the proton gradient constitutes the proton motive force that constitutes the basis for adenosine triphosphate (ATP) gen- eration via oxidative phosphorylation [73]. It regulates mitochondrial

Fig. 1. Factors of mitochondrial tness.

Nutrients such as glucose or fatty acids enable tricarboxylic acid (TCA) cycle activ- ity and oxidative phosphorylation (OXPHOS). During OXPHOS reactive oxygen species (ROS) are produced and ROS-levels are massively increased, when the OXPHOS system is dysfunctional. Mitochondria are directly involved in the innate immune response and in ammation by RIG-1 like receptor (RLR) activated mitochondrial antiviral signaling (MAVS) system and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) in ammasome interac- tion. Mitochondria can change their morphology by fusion or ssion with func- tional implications, for example on mito- chondrial localization, mitochondrial quality control or bioenergetics ef ciency. They in- crease their numbers or density by mito- chondrial biogenesis and control cell death and differentiation. An important alternative pathway to OXPHOS to generate energy in the form of adenosine triphosphate (ATP) is glycolysis.

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import and export and the fate of mitochondria: alterations in MMP can induce mitophagy or cell death [74]. ROS, calcium uxes or viral in- fections can all modulate MMP [64]. Viruses manipulate MMP to either improve cell survival for viral replication and to prevent apoptosis in response to infection or they promote apoptosis, for example for virion release [64,75,76].

The centerpiece of the mitochondrial anti-viral machinery, MAVS, has been demonstrated to depend on MMP [77]. Mitochondria with compromised MMP thus are less ef cient in the anti-viral host defense. Supporting this notion, compromised MMP results in diminished cyto- kine production after infection with various RNA viruses [78]. Accord- ingly, some viruses (e.g., in uenza virus) reduce MMP to inhibit MAVS [79].

Together these data suggest that modulation of MMP by viruses renders mitochondria less capable for antiviral defense and more sus- ceptible for further viral manipulation.

3.2. Oxidative phosphorylation versus glycolysis

The MMP is established by the electron transport system, consisting of the mitochondrial protein complexes I – IV. The resulting chemical potential and the proton gradient between mitochondrial matrix and inter-membrane space is used for ATP-production by ATP-synthase. This process is called oxidative phosphorylation and is the main source of chemical energy in most cells of the human organism. Defects of oxidative phosphorylation, for example complex I [80], are associate with the production of higher levels of ROS that may induce in am- mation. Indeed, modulation of in ammatory responses by the electron transport system has recently been shown [81].

MAVS-mediated innate anti-viral signaling also depends on oxidative phosphorylation. This has been demonstrated in cells with oxidative phosphorylation de cits, which are less ef cient in mounting anti-viral host responses and induction of interferons and cytokines [82]. Func- tional mitochondrial respiration is furthermore required to activate specialized immune cells, usually followed by reduced mitochondrial respiration of many of these cells during infection, when glycolytic uxes are elevated [59,60]. For SARS-CoV-2 several potential direct interactions of viral proteins with the electron transfer system have been reported [83,84] suggesting that oxidative phosphorylation de cits occur in COVID-19.

Viral infection is generally associated with increased reliance of cells on glycolysis for energy production, potentially establishing optimal conditions for viral replication. This phenomenon is for example well described for Dengue [85] and Hepatitis C Virus [86]. On the level of the lung, chronic inhibition of mitochondrial respiration also leads to a metabolic switch to glycolysis, impedes alveolar gas exchanges and ventilator adaptation to match blood oxygen content with oxygen de- mand [87,88], leading to oxygen desaturation. Resulting low alveolar oxygen pressure leads to in ammatory responses by activation of lung cells and in particular alveolar macrophages [89].

3.3. Mitochondrial antiviral signaling

Viruses have developed a vast repertoire to inhibit MAVS activity on multiple levels, from pathogen detection to interferon signaling [63]. Interferons are an integral cellular weapon against viruses. An inade- quate immune reaction has been reported for SARS-CoV-1 [90] and SARS-CoV-2 [47], characterized by low interferon activation, but high levels of pro-in ammatory cytokines. Apart from suggesting this dys- regulation to be involved in severe COVID-19 linked cytokine storm formation, it also indicates viral usurpation of host MAVS. For SARS-CoV-1 there is indeed a large body of evidence of mitochondrial antiviral host defense involvement modulation [91,92], including for example the inhibition of RIG-1 and MAVS by viral proteins. Such mechanisms are expected to be at work similarly in COVID-19 [51].

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3.4. Oxidative stress

Oxidative phosphorylation is a major source of ROS. Although mitochondrial ROS have important roles in cellular signaling regulating amongst others life-span [93], excessive ROS levels lead to oxidative stress and are linked to damage to mitochondrial DNA and tissue. The proximity of mitochondrial DNA to the sites of oxidative phosphoryla- tion renders it particularly vulnerable to oxidative damage.

Upon infection mitochondria increase ROS production as a defense mechanism or due to damage caused by the infection. Various viruses have developed strategies to modulate mitochondrial ROS generation, for example to promote survival of the host cell and viral replication, and/or to pro t from pro-oxidant conditions [62,64]. For viral respira- tory infections it has been shown that the endogenous antioxidant sys- tems can be suppressed [94]. While the knowledge on ROS and oxidative stress in SARS-CoV-2 is very limited, several indications of mitochon- drial damage and oxidative stress suggest a role of ROS in infection and disease progression: viral RNA deposition in mitochondria [68], inter- action of viral proteins with components of the electron transport system [83,84] and oxidized phospholipids in the lungs of SARS patients [95].

3.5. Mitochondrial biogenesis

Mitochondrial biogenesis is the increase of mitochondrial mass from pre-existing mitochondria and is regulated by the co-transcriptional factor peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) and other factors [96,97]. PA or dietary restriction induce several regulators of mitochondrial biogenesis, for example AMP-activated protein kinase (AMPK), which in turn activates PGC-1α. In conjunction with a number of other transcription factors, PGC-1α activates mitochondrial transcription factor A (TFAM), leading to mitochondrial growth and eventually formation of new mitochondria by division [98]. Together with its coactivators, PGC-1α (and also PGC-1β) furthermore are involved in the generation of anti-in ammatory cellular environments following PA [99].

SARS-CoV-1 has been suggested to interact with prohibitin proteins [100] that in uence mitochondrial biogenesis and fusion [101]. The regulation of mitochondrial biogenesis by viruses, not to mention SARS-CoV-2, in general is, however, poorly understood.

3.6. Mitophagy

Dysfunctional mitochondria are hazardous for cells as they release toxic substances, including ROS and cell-death regulating factors. They can get targeted to and engulfed by autophagosomes and eventually get degraded by the lysosome in a process referred to as mitophagy, a major cellular mechanism of mitochondrial quality control. Criteria for mito- phagic clearance of mitochondria include dysregulated MMP and oxidative phosphorylation or mitochondrial DNA mutations [102].

Of potential relevance for COVID-19 is the observation that hypoxic conditions promote mitophagy [103]. Severe SARS-CoV-2 infection is characterized by reduced oxygen provision and the induction of mitophagy could be bene cial with regard to the clearance of virally compromised mitochondria and to tissue integrity. As discussed below, however, SARS-CoV-2, may promote mitochondrial fusion [104], potentially counteracting hypoxia-induced mitophagy.

3.7. Mitochondrial dynamics and traf cking

“Mitochondrial dynamics” denominates the processes of mitochon- drial fusion and ssion by division of mitochondria. In contrast to mitochondrial biogenesis and mitophagy, mitochondrial dynamics do not change mitochondrial mass. The main effectors for fusion of the outer mitochondrial membrane are mitofusin 1 (MFN1) and MFN2, for fusion of the inner mitochondrial membrane optic atrophy 1 (OPA1) and for ssion dynamin-related protein 1 (DRP1). While fused mitochondria

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exhibit more ef cient oxidative phosphorylation and exchange of me- tabolites and mitochondrial DNA [105], ssion may facilitate shuttling of mitochondria to different cellular locations, for example for cell membrane repair [106], and to clear away damaged mitochondria by mitophagy [103].

Viral infection entails re-modelling of mitochondria [62]. On one hand, mitochondrial dynamics regulate MAVS [107]. Speci cally, mitochondrial fusion has been proposed to be bene cial for MAVs ac- tivity, which is why elongated mitochondria may be common during viral infection [108–110]. On the other hand, viruses modulate mito- chondrial dynamics and interestingly this can promote either fusion or ssion depending on the viral species. SARS-CoV-1 has been reported to induce the degradation of the ssion factor DRP1 [111], presumably favoring fusion.

Mitochondrial tness of systemic and resident immune cells is furthermore crucial for the coordinated immune response [112] that is compromised in COVID-19 [113]. While the importance of mitochon- drial metabolism (and its coordination with glycolysis-derived energy supply) in specialized immune cells for their activation, differentiation and immune function is now well established, the metabolic differences of speci c immune cell types and the mechanisms and associated con- sequences of immunometabolism regulation are currently under heavy investigation [114–116].

Taken together, disruption of mitochondrial functions in cells infected by RNA-viruses is a common phenomenon. Speci c virulence mechanisms but also the immune response of the host cell contribute to mitochondrial dysfunction. Whether this could mean that pre-existing mitochondrial dysfunction aggravates viral infection by for example SARS-CoV-2 and whether improving mitochondrial tness may confer protective effects, is discussed below.

4. Low cardiorespiratory and mitochondrial tness as risk factors for COVID-19?

A number of pre-conditions, including cardiovascular diseases, dia- betes, chronic obstructive pulmonary disease (COPD) – and maybe obesity – but especially advanced age dramatically increase the risk of severe outcome of SARS-CoV-2 [117,118]. Mitochondrial dysfunction, tightly linked to oxidative stress, reduced immune response and chronic in ammation, and an associated low cardiorespiratory tness may be mediating this risk. Indeed, regular PA and increased cardiorespiratory tness bene cially affect mitochondrial tness, as outlined below.

4.1. The association of cardiorespiratory and mitochondrial tness

PA determines cardiorespiratory tness and triggers mitochondrial plasticity that can induce enhanced mitochondrial tness. The resulting bene ts on mitochondrial tness include mitochondrial biogenesis, mitochondrial respiration, mitochondrial protein synthesis and enzyme activity, better oxidative stress handling and higher mitochondrial ox- ygen af nity (which denotes the oxygen pressure at the level of mito- chondria at which the mitochondrial respiration is 50% of the maximal rate of mitochondrial respiration at saturating oxygen concentrations) [97,119-123]. These effects induce reduced reliance on anaerobic glycolysis, improve fatty acid oxidation and can increase aerobic per- formance [124]. High mitochondrial tness furthermore correlates with exercise performance and health [125–127], even at advanced age [128]. Regular exercise induced bene cial mitochondrial changes are especially well known for skeletal muscle [42,97,129] and reversely well-functioning mitochondrial networks are crucial for regulation of skeletal muscle mass and function [130]. Bene ts of PA for mitochon- dria have, however, also been reported for other tissues, such as the heart, kidney and liver [15,16] as well as for the brain [16–18], gonadal tissue and pancreas [19] and the lung [20]. Chronic moderate exercise is believed to exceed muscle adaptations (reviewed for example by Refs. [21,131]) and boost mitochondrial function also in distant organs. This

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may be possible due to auto-/para-/endocrine skeletal muscle feedback [16] e.g. directly by myokines [132] or exosome/microvesicle-transported “exerkines” [19]. Furthermore, in- direct exercise-modulated factors such as systemic temperature or baro- and chemoreceptor sensing may be involved in enabling “reprogram- ming” also of distant tissues, regulating for example metabolism and immunity [39].

It can thus be assumed that mitochondria – and therefore innate immune responses to SARS-CoV-2 – in many tissues pro t from PA. This is particularly relevant in light of increasing evidence of SARS-CoV-2 infection of tissues (including heart, kidney, liver, brain, etc.) other than the respiratory tract [113,133], that remains the primarily affected organ in COVID-19 [134], and associated organ-speci c diseases [113] and immune responses [135].

Importantly, remodeling of mitochondrial functions can be controlled by the selection of different types of exercise, duration and intensity [123,136], in theory enabling targeted exercise intervention to modulate speci c mitochondrial functions. Granata and colleagues [137] recently provided excellent guidelines for exercise program pre- scriptions with particular consideration of mitochondrial biogenesis. Conversely, a sedentary lifestyle or prolonged inactivity (i.e., large reduction of PA), such as may occur during quarantining associated with the COVID-19 pandemic [2,3], leads to both reduced mitochondrial content and function [123]. Here we discuss several well described ef- fects of exercise on parameters of mitochondrial tness (Fig. 2) that may be harnessed to mitigate viral infection risk and severity.

4.1.1. Mitochondrial biogenesis and oxidative phosphorylation

Mitochondrial biogenesis and oxidative phosphorylation capacity are the best studied mitochondrial adaptations to exercise. Although they are most likely strongly linked, they do not necessarily depend on each other [122].

Similar metabolic adaptations, including for example PGC-1α upre- gulation and increased lipid oxidation, were reported for low-volume, high exercise (sprint interval training) and high-volume, moderate in- tensity endurance training [138]. Higher intensity at similar volumes, however, may have even more pronounced bene cial effects on mito- chondrial respiration [139]. The greatest effects on mitochondrial respiration may be induced by a combination of moderate-intensity and high-intensity exercise training [123]. The modulation of training vol- ume, on the other hand, has been suggested to have a more important impact on mitochondrial content/density mediated by mitochondrial biogenesis [123].

Already acute responses to single bouts of high intensity exercise (de ned as: including intervals performed above 75% of the maximal power achieved during an 8- to 12-min graded exercise test) can induce metabolic changes resulting in transcriptional upregulation of proteins related to mitochondrial biogenesis, fatty acid oxidation, the Krebs cycle, and oxidative phosphorylation [122]. At the same time nuclear signaling molecules interact with mitochondria and mitochondrial protein synthesis is increased. Repeated bouts of exercise and associated repeated stimulation of mitochondrial protein synthesis and mitochon- drial dynamics (especially mitochondrial fusion) results in enhanced mitochondrial biogenesis, function and morphology [122].

Mitochondrial biogenesis effects may be also be increased at higher intensities [122], despite the potential main modulatory effect of vol- ume [123]. Several exercise sessions per day could be superior to single exercise sessions per day (at same total exercise sessions) [122] and combination with resistance training has been shown to render the mitochondrial adaptations, in particular respiration, more robust [140].

4.1.2. Mitochondrial dynamics and quality control

Given the dependence of both mitochondrial biogenesis and oxida- tive phosphorylation on mitochondrial dynamics, it is not surprising that a single bout of exercise affects mitochondrial morphology. This effect is more subtle in moderate [141] and more pronounced at high intensity

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Fig. 2. Parameters of mitochondrial tness in different tissues that can be modulated by physical activity (PA). Speci c effects on distinct tissues are shown only for chronic moderate intensity PA due to the scarcity of data for other conditions. Effects that are potentially more pronounced than in other modalities and may represent distinguishing features are highlighted in red. While the indicated effects of PA on mitochondrial functions are established for human skeletal muscle, evidence on mito- chondrial bene ts in remote tissues are more scarce. While enhanced mitochondrial biogenesis, oxidative phosphorylation (OXPHOS) and anti-oxidant capacities have been convincingly shown in response to PA in various tissues in rodents [16], more research is needed to fully understand exer- cise effects on mitochondria. However, ro- dent pathology models support the assumption of the potential of PA to rescue mitochondrial tness also in other tissues [19] and for other mitochondrial functions, such as mitochondrial dynamics [232]. This aspect has recently been discussed for human brain [233] and the mode of

[234]. ROS – reactive oxygen species. . (For interpretation of the references to colour demonstrated in animal experiments by the quanti cation of the mito-

phagic ux 97. In humans, an equivalent effect may be most pronounced with lifelong exercise, while chronic exercise training (4 months) seems to be associated mainly with improved mitochondrial fusion [147].

4.1.3. Antioxidative capacities

Although ROS-signaling is involved in mediating the previously discussed bene cial adaptations to exercise [97,148–150], ROS-induced oxidative stress can have detrimental consequences [151,152]. An improved antioxidative status can be achieved by exercise, especially by regular moderate exercise [151]. High intensity exercise, in particular in repeated bouts, more likely induces oxidative stress-linked damage [153]. Improved anti-oxidative capacities as a consequence of PA [154–156] is supposedly protective by preventing mitochondrial, cellular and tissue damage in conditions of oxidative stress, such as for example in in uenza infection [157]. Aging, on the other hand, reduces antioxidant capacities; an effect that, however, can partly be prevented by life-long regular exercise [154]. Other effects of aging on mito- chondrial and cardiorespiratory tness are discussed in the next section.

4.2. Cardiorespiratory and mitochondrial tness in aging

Aging is associated with a functional decline of various organs; for example oxygen uptake is impaired by compromised lung function [158], an age-related ventilation-perfusion mismatch [159] as well as endothelial and vasculature dysfunction [160] resulting in arterial stiffness. Also, the heart becomes more susceptible to disease [161]. In line with these alterations, also cardiorespiratory tness decreases massively with age; in the general population cardiorespiratory tness drops by around 10% per decade after an age of 30 [162]. Regular PA can considerably delay and decrease this decline [163,164].

Supporting the strong correlation with cardiorespiratory tness, also mitochondrial tness declines with aging, as evidenced by increased mitochondrial DNA mutations and oxidative stress, as well as less ef – cient mitochondrial dynamics, biogenesis, MMP and quality control[98, 165-169]. Interestingly, mitochondrial ATP-production capacity has been estimated to be reduced by around 8% per decade [170] and age-related mitochondrial tness decline may also be mainly due to

communication of PA effects to other tissues has been outlined recently as well in this gure legend, the reader is referred to the Web version of this article.)

exercise bouts [122] and relies mainly on the modulation of mito- chondrial fusion, facilitating inter-mitochondrial exchange of metabo- lites and mitochondrial DNA [97]. Mitochondrial fusion possibly also enhances the immune system by optimizing both respiration and contact with STING-component associated endoplasmic reticulum membranes, resulting in a more effective interferon activation and host response [107–109]. In agreement with this hypothesis, knocking out the pro-fusion factors MFN1 and MFN2 in mice reduced interferon and cytokine induction in response to viral infection with the RNA virus Sendai Virus [77]. Whether enhanced mitochondrial fusion renders mitochondria more resilient during coronavirus infection is however questionable: other SARS-CoVs appear to modulate mitochondrial dy- namics by degrading DRP1 [104], thus also favoring fusion. This could mean that acute physical exercise may exacerbate the shift of the mitochondrial dynamics homeostasis by promoting even stronger pre-fusion conditions. The degradation of DRP1 possibly impairs the clearance of dysfunctional – for example viral RNA or protein containing – mitochondria and thus potentially supports survival of the infected cell during viral replication. Most likely the effects of regular PA on the dynamic nature of mitochondrial networks and the stimulation of mitophagy are still reducing COVID-19 infection risk. Intriguingly, both exercise and SARS-CoVs may enhance mitochondrial fusion. How these two pro-fusion effects interact has not been investigated. It is possible that acute exercise-induced mitochondrial fusion supports the manipu- lation of mitochondrial dynamics by the virus, potentially promoting virulence. This possibility supports existing guidelines recommending to refrain from exercise in case of suspected SARS-CoV-2 infection [142] and reduce PA in dependence of symptom severity [143].

Long-term exercise strongly remodels mitochondria; it enhances fusion by increasing the expression of Opa1 and Mfn2, while also reducing the ssion factor Drp1 97 and may induce increased cristae density [144] and modulate supercomplex formation [145]. Lifelong voluntary exercise (free access to running wheels) nally is capable to prevent age-related mitochondrial fragmentation in mice [146].

Both acute and regular exercise furthermore improve mitochondrial quality control and turnover by stimulating mitophagy, facilitating ATP production and resulting in improved lipid metabolism and reduced muscle mass loss and apoptosis 97. These effects have been

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physical inactivity [171], both corresponding well with the decrease in cardiorespiratory tness. Indeed, bene cial mitochondrial adaptations in response to exercise have been reported to be largely independent of age [140]. On the other hand, a reduced mitochondrial plasticity in age may cause an attenuated mitochondrial response to exercise [97].

Unsurprisingly, the decline in mitochondrial tness is also associated with a concurrent deterioration of the immune system [172], including impaired interferon responses [173]. Mitochondrial dysfunction [120], oxidative stress [174] and in ammation mediated suppression of im- munity are well characterized features of aging [175]. The related term “immunosenescence” [176] denotes a state of an aged immune system that is characterized by reduced ef ciency, but as well by an intensi ed innate immune response leading to increased risk of tissue damage due to the immune response and to a higher risk of in ammatory disease and other associated age- and obesity-related diseases [23,177]. Recent ndings on the effects of mitochondrial dysfunction in T-cells, which increased chronic in ammation and accelerate senescence in mice furthermore suggest a causal involvement in mitochondrial dysfunction of immune system components in aging [178]. The role of immunose- nescense in COVID-19 and the related potential of targeting immuno- metabolism has recently been discussed in more detail [179].

In line with the effects of PA on mitochondrial and cardiorespiratory tness, lifelong exercise has been shown to mitigate age-related increased in ammation [180].

In summary, the presented effects of aging at least partly explain the increased susceptibility and vulnerability to viral infections, including in uenza [181,182] and COVID-19 [183,184] in the older population. Importantly, however, these risk factors can be largely reduced by reg- ular PA.

4.3. Cardiorespiratory and mitochondrial tness and COVID-19 comorbidities

Apart from age, several pre-conditions, notably including cardio- vascular and respiratory diseases like COPD increase risk of COVID-19 infection and severe disease progression [117]. Importantly, also these comorbidities of COVID-19 are characterized by reduced cardiorespi- ratory tness [185] and associated with mitochondrial dysfunctions.

Epidemiological studies clearly link cardiorespiratory tness to the risk of developing cardiovascular disease [186] and dying from it [186]. Accordingly, mitochondrial dysfunction is common in cardiovascular diseases as well [187] and includes increased mitochondrial DNA damage [188] and mitochondrial ROS production, as well as de cits in oxidative phosphorylation, mitochondrial morphology and quality control [189].

Also for COPD low cardiorespiratory tness is a major risk factor [190]. COPD patients exhibit reduced mitochondrial respiration ca- pacities, which may be exacerbated in combination with low body mass index [191]. Speci cally, human airway smooth muscle cells from COPD patients are characterized by reduced MMP, reduced mitochon- drial respiration capacities, and increased ROS [192]. Viral respiratory infection furthermore is involved in the etiology of – or exacerbates – COPD and several other chronic diseases [193], highlighting the po- tential long-term effects of SARS-CoV-2 infections on public health.

High cardiorespiratory tness is an important protective factor for cardiovascular disease [194] and COPD [195] rendering these COVID-19 comorbidities largely amenable to PA. Mitochondrial tness is a strong candidate to mediate the bene cial effects of regular PA, also by improving immune system function and reducing in ammation [196, 197].

Consequently, obesity and diabetes have been discussed to represent further risk factors for COVID-19 severity [198–205]. This is in line with reported negative consequences of obesity on viral infection and im- munity that have previously been reported [206,207] and recently been reviewed [205,208,209]. Among the most relevant detrimental conse- quences of inactivity and elevated body fat content for viral infections

Redox Biology 43 (2021) 101976

are increased oxidative stress and in ammation [210]. The adverse ef- fects especially of unhealthy adipose tissue with regard to COVID-19 have been discussed in more detail elsewhere [12].

Cardiorespiratory tness until now has been scarcely considered as an independent modi er of COVID-19 [43,45]. This is surprising due to previous ndings suggesting that negative consequences of obesity (body mass index or waist circumference) on general mortality may be mediated by cardiorespiratory tness [211,212].

In summary, compromised immune function and in ammation in aging, sedentary lifestyle and chronic diseases – all interdependently linked to mitochondrial dysfunction – represent pre-dispositions for viral infections including SARS-CoV-2. This implies that avoiding these conditions or preventing their aggravations could strongly mitigate SARS-CoV-2 infection risk and outcome and PA has the potential to do just that.

5. The protective potential of PA in COVID-19

As outlined in this review, regular PA and high mitochondrial and cardiorespiratory tness can increase the antiviral immune response and reduce basal levels of in ammation and oxidative stress. In addition, PA could counteract COVID-19 related lung, vascular and blood abnor- malities and thus improve oxygen supply to enhance mitochondrial tness, both in specialized immune cells and in target tissues. Acute high-intensity exercise during infection or at risk for infection could, however, be detrimental by negatively impacting on redox status and immune function.

5.1. Blood and vasculature

Adequate oxygen supply relies on a functional vasculature that is capable to control the transport of blood. With age, vascular functions are impaired, mediated in part by impaired endothelial nitric oxide synthase (eNOS) activity [160]. Oxidative stress, lung in ammation and potential direct vascular damage by viral infection also impede blood transport, for example by coagulation dysregulation [213]. Coagulation is a common response to in ammation and low platelet counts and coagulation abnormalities may be associated with adverse outcomes of SARS-CoV-2 infection [213]. PA is essential to maintain vascular integrity. Already ve days of reduced PA were suf cient to impair vascular function in young, recreationally active men [214]. This was manifested in artery ow mediated dilation de cits and elevated plasma concentrations of endothelial micro particles indicating activated or apoptotic endothelial cells. A direct association of mitochondrial respi- ration on immune responses in human blood cells has been recently demonstrated; inhibition of particularly mitochondrial complex IV in this study impaired cytokine induction [81].

5.2. Lung mitochondria

Little information is available on the effect of exercise on mito- chondrial dysfunction in the lung following respiratory infection. However, in a rodent study of experimental lung injury by intratracheal instillation of lipopolysaccharide, reduced mitochondrial complex II activity in the lung and formation of lung edema was observed [20]. Two weeks of exercise before the intervention rescued both of these effects. In another study using the same mouse model, but no exercise intervention, the observed severe mitochondrial dysfunction in pulmo- nary epithelia as well as associated pathologies and mortality were rescued by provision of healthy mitochondria transferred to the lung cells from exogenously applied bone-marrow derived stromal cells [215].

5.3. Exercise recommendations

Given the pronounced PA bene ts against viral infection, the

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question arises, how to best take advantage of this knowledge. Based on the information assembled in section 4.1 and summarized in Fig. 2, some recommendations for suitable forms of exercise to boost mitochondrial tness with the speci c aim to strengthen anti-viral immune defenses is provided in Table 1. Of course, the selection of training programs de- pends on the immediacy of infection risk. As outlined above, even single high intensity exercise bouts transiently put tremendous stress on mitochondria, increase oxidative stress, reduce immune function and thereby could facilitate viral replication, cell death events and – in the case of COVID-19-induced acute cardiac injury – a proarrhythmic myocardial substrate [216]. Especially eccentric – but also other types of strenuous – exercise furthermore are associated with increased systemic in ammation [38], a dangerous mechanism in the context of COVID-19. Intensive exercise thus should not be performed during infection, sus- pected infection, persisting illness or symptoms, and not for at least 1–2 weeks after complete symptoms resolution. On the other hand, bene – cial systemic and mitochondrial adaptations and anti-in ammatory ef- fects of moderate exercise [28,29], as well as a high cardiorespiratory tness – that is also associated with low in ammation [23] – resulting from regular exercise are likely important protective factors for COVID-19. For Table 1, high intensity training (HIT) is considered as a training including intervals performed at >75% of the maximal capac- ity). Moderate intensity training (MIT) is usually performed at around 50–75% of the maximal capacity, often in a continuous fashion (MICT). A detailed review on the effects of exercise intensity on mitochondrial parameters has been published in this journal [123]. Beside intensity, the exercise modality determines mitochondrial outcomes. While mitochondrial bene ts, in particular of mitochondrial biogenesis, are very well established for endurance exercise, they are less well under- stood for resistance exercise. Resistance exercise, however, is an attractive exercise modality also to be performed at home and thus relevant for COVID-19 associated limitations of mobility. Porter et al. [217] reported that 12 weeks of resistance exercise enhanced mito- chondrial respiration and mildly increased expression of mitochondrial transcripts and proteins. This indicates that endurance and resistance

Table 1

Suggested exercise interventions for infection risk reduction.

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exercise differentially – and possibly synergistically – boost mitochon- drial tness; a hypothesis that deserves further scienti c exploration.

In summary, plasticity of skeletal muscle mitochondria in response to regular exercise [42,97,129] improves mitochondrial tness parame- ters, such as energy provision, biogenesis, optimization of mitochondrial dynamics and higher anti-oxidative capacities. Stimulation of skeletal muscle adaptations, including of mitochondria, then allows a metabolic re-programming – possibly improving mitochondrial tness – also of distal tissues [39], such as of the lung [20], the primarily affected organ by SARS-CoV-2 infection [134]. Improvements of mitochondrial tness in the lung, as well as in other tissues affected by COVID-19 [113,133] are expected to improve the innate immune function [51] – and there- fore reduce infection probability – of these target tissues. The key role of mitochondria in the activation and ef ciency of specialized immune roles is also becoming increasingly acknowledged [40,41] and is being discussed more and more in the context of COVID-19 [179,218–220]. In addition, the bene cial effects of regular PA on cardiorespiratory tness and on in ammation may be protective for the important COVID-19 symptoms hypoxemia [221,222] and cytokine storm [67].

Regular moderate PA via its bene cial effects on mitochondria and consequences on innate immune system of potential target tissues for SARS-CoV-2 infection, oxidative stress, in ammation, adaptive immune and vascular systems possibly reduces viral infection and most likely decreases disease severity and mortality. Acute high intensity exercise, on the other hand may facilitate viral infection via a debated transient reduction of the immune system capacity [37,223]. If performed during infection, it may also aggravate disease progression and mortality. While at risk for infection, or after contraction of SARS-CoV-2, caution is thus necessary for the engagement in PA. Nutritional and pharmacological strategies to enhance mitochondrial involvement in the innate immune function may be preferable alternatives under these conditions [51]. Although the here highlighted preliminary evidence indicates that reg- ular PA-mediated mitochondrial tness may be protective against COVID-19, many questions remain open. These include the speci c ef- fects of exercise intensity, modality and frequency on infection risk, severity of disease and mortality. In addition, the role of tissue-speci c mitochondrial tness in COVID-19 – and generally in infectious diseases – is poorly understood: Will improved tness of skeletal muscle mito- chondria following PA suf ciently boost mitochondrial tness of distal tissues to protect from COVID-19? Does improved mitochondrial tness of the respiratory tract reduce the likelihood of viral infection? Does mitochondrial tness e.g. in heart and brain protect from secondary effects of viral infection on these tissues? Which forms of exercise will best improve the metabolism of specialized immune cells to act against viral infection, and which forms of exercise might even reduce the host immune defense?

6. Conclusions and practical considerations

Beside the well-known roles of mitochondria in energy-production, oxidative stress regulation, ion-homeostasis, metabolite-synthesis, and many others that directly and indirectly contribute to the systemic im- mune response to infections, direct mitochondrial involvement in innate immunity has emerged as another important function of the organelle. Viral infections, for example by SARS-CoV-2, compromise mitochon- drial functions. SARS-CoV-2 strikingly has more adverse effects on population groups characterized by elevated levels of in ammation and mitochondrial dysfunction, such as older or obese people or individuals suffering from cardiovascular or pulmonary diseases. Based on the strong association of mitochondrial and cardiorespiratory tness, we put forth the hypothesis that enhancing mitochondrial tness by regular PA is a protective factor in COVID-19. Regular PA and mitochondrial tness enhance redox and in ammatory status and ameliorate the immune response to infection. In addition, they have clear preventive potential on many chronic diseases that are considered to be risk factors for COVID-19 outcome and counteract several detrimental aging-related

SARS-CoV-2: potential effects on host mitochondria

Reduced OXPHOS

Reduced MAVS

Increased oxidative stress

Reduced biogenesis

Impaired mitophagy

Impaired dynamics

Absence of infection risk (e.g. no pandemic or complete isolation)

1. regular HIT
2. regular MIT for best effects include resistance training and combine high and low intensity 1. regular MIT
2. regular HIT

1. regular MIT 2. regular HIT

1. regular MIT (higher intensity, repeated bouts per day and high volumes may increase effect)

2. regular HIT 1. regular MIT 2. regular HIT regular MIT or HIT

Infection risk (during the pandemic, not isolated)

regular MIT

regular MIT avoid acute HIT
regular MIT avoid acute HIT

regular MIT

regular MIT regular MIT

During infection/ recovery

avoid exercise during infection and follow published guidelines for re-uptake of exercise after a recovery period of at least 1–2 weeks of convalescence [142, 143,216,235,236]

  

Explanations: HIT – high intensity training, MIT – moderate intensity training, SARS-CoV-2 – Severe Acute Respiratory Syndrome Coronavirus 2, OXPHOS – oxidative phosphorylation, MAVS – mitochondrial anti-viral signaling.

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processes that may also be associated with higher COVID-19 risk. The necessary political measures to reduce viral spreading, including various lockdown and isolation strategies, for example in the context of contact tracing lead to increases in sedentary lifestyle and inactivity, especially in vulnerable individuals [224,225]. This effect is further aggravated by reduced possibilities to practice sports in gyms, tness centers and sports clubs. Based on the well-established general bene ts of regular PA on chronic diseases and all-cause mortality [8], mental health [3], as well as on incidence and mortality speci cally in viral infections, such as in uenza [226–228], COVID-19-related reductions in PA are likely to entail massive global health and socio-economic consequences. Impor- tantly, already low volumes of exercise can pronouncedly improve mitochondrial [42] and cardiorespiratory tness [229], in particular at low baseline tness levels. Regular exercise is thus an ef cient way to promote public health even at low time and cost investment. Conversely, reduced exercise volumes and sedentary lifestyle quickly result in decreased mitochondrial tness [125]. The bene ts of reduced seden- tary times have recently been prominently discussed with regard to the World Health Organization 2020 guidelines on physical activity and sedentary behavior [230], the bottom lines of which are that already low levels of PA are bene cial but more PA further improves health outcomes.

With regard to the ongoing COVID-19 pandemic, regular moderate exercise and higher PA levels in summary have the potential to enhance immune system functions via improving mitochondrial tness. It is thus even more important during isolation and con nement periods to maintain workout-routines and avoid the reduction of PA; e.g. by making sure to reduce sitting times (standing or walking whenever possible during private or professional tasks and interrupt prolonged sitting with periods of PA), walking as much as possible (instead of driving, using elevators, etc.) and as often as possible perform workouts. These workouts may be endurance trainings (e.g. using cycle or rowing ergometers, climbing stairs, etc.), resistance training (e.g. using dumb- ells or thera bands), dancing, yoga, tai chi or other forms of exercise. Different exercise modalities have overlapping but also differential ef- fects, also on mitochondrial tness [217], and thus performing workouts sessions of varying exercise modalities may be particularly useful to improve various mitochondrial functions. Importantly, direct mito- chondrial improvements after exercise in the skeletal muscle are accompanied by increased mitochondrial tness of specialized immune cells and other tissues that are relevant for COVID-19 as outlined above. Strenuous exercise should be performed cautiously during the pandemic. As discussed, bouts of intensive exercise (from around >60% of maximal oxygen uptake/heart rate reserve or of durations of >60 min [23]) may transiently decrease immune function and facilitate viral infection. It is possible that this effect is also related to mitochondrial tness; depletion of energy levels following physical exertion, as well as increased redox signaling/oxidative stress and in ammatory mitochondrial-damage signals rst in skeletal muscle and then in the immune system and remote tissues [16,39]. The primary target tissue of SARS-CoV-2, the respiratory tract, might furthermore be directly affected by oxidative stress and mitochondrial dysfunction as a conse- quence of increased ventilation during high intensity exercise, although this seems not to be the case in healthy subjects as suggested by rodent experiments [231]. Taken together, high intensity exercise is thought to open up an ill-de ned window of infection-vulnerability [37] and thus should be avoided whenever there is a risk of SARS-CoV-2 infection.

We conclude that mitochondrial and cardiorespiratory tness most likely are important – and modi able – protective factors for COVID-19, possibly representing a link between a number of established risk fac- tors. We argue for regular analysis of COVID-19 patients’ cardiorespi- ratory tness that may be a modulator of disease severity and mortality. The promotion of mitochondrial tness, e.g. by PA, may be a protective measure against viral infection. At the same time the consideration of the potential dangers of high-intensity exercise during or short after the viral phase as facilitator of infection and maybe disease severity is of

Redox Biology 43 (2021) 101976

9

great importance.

Declaration of competing interest

All authors contributed to writing the manuscript, all read and agreed to submit the nal version of it.

The authors declare no con icts of interest related to the topic of this review.

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