Exercise is the Most Important Medicine for COVID-19

Abstract

COVID-19 infection and long COVID affect multiple organ systems, including the respiratory, cardiovascular, renal, digestive, neuroendocrine, musculoskeletal systems, and sensory organs. Exerkines, released during exercise, have a potent crosstalk effect between multiple body systems. This review describes the evidence of how exerkines can mitigate the effects of COVID-19 in each organ system that the virus affects. The evidence presented in the review suggests that exercise should be considered a first-line strategy in the prevention and treatment of COVID-19 infection and long COVID disease.

Full text

Exercise is the Most Important Medicine
for COVID-19
Georgia Torres, PhD;
1
Demitri Constantinou, MBChB, FACSM;
1
Philippe Gradidge, PhD;
1
Deepak Patel, MD;
2
and Jon Patricios, MBBCh, MMedSci
3
Abstract
COVID-19 infection and long COVID affect multiple organ systems,
including the respiratory, cardiovascular, renal, digestive, neuroendocrine,
musculoskeletal systems, and sensory organs. Exerkines, released during
exercise, have a potent crosstalk effect between multiple body systems.
This review describes the evidence of how exerkines can mitigate the effects
of COVID-19 in each organ system that the virus affects. The evidence
presented in the review suggests that exercise should be considered a
first-line strategy in the prevention and treatment of COVID-19 infection
andlongCOVIDdisease.
Introduction
The worldwide presence of COVID-19 infections continues
with sporadic spikes in infection numbers (1). The virus af-
fects multipleorgan systems, including the respiratory, cardio-
vascular, renal, digestive, neuroendocrine, musculoskeletal
systems, and sensory organs (2). In addition, long COVID
(postacute sequelae of COVID-19 [PASC]) has been identified
as a post COVID-19 infection condition that affects at least
65 million individuals worldwide (3). This chronic disease im-
pacts heart, lung, pancreas, kidney, spleen, liver, blood vessels,
and the neurological, gastrointestinal, immune, and reproduc-
tive systems with a wide variety of pathology (3). Furthermore,
COVID-19 infection and long COVID increases the risk of med-
ical conditions, including cardiac arrest, heart failure, stroke,
pulmonary embolism, diabetes, myalgic encephalomyelitis, and
dysautonomia with breakthrough afflictions of coagulation, he-
matological, pulmonary, and neurological conditions (3). There
are currently no validated effective treat-
ments for long COVID (3).
Consistently meeting physical activity
guidelines has been associated with re-
duced risk of severe COVID-19 infection
outcomes, i.e., hospitalization (22% to
42% reduction), ICU admission (34%
to 38% reduction), deterioration, and
death (43% to 83% reduction) (4–7),
across demographic and clinical charac-
teristics (8). Furthermore, those engaged
in regular physical activity have an 11%
to 22% lower risk of infection (6,9–11). The greatest benefit is
provided by achieving at least 500 metabolic equivalent of task
(MET)-min per week of physical activity, which is equivalent
to 150 min of moderate-intensity or 75 min of vigorous-intensity
physical activity per w eek (6). Studies also have found that car-
diorespiratory fitness (CRF) is a predictor of COVID-19 disease
progression and mortality (5,12,13).
Exerkines are signaling moieties that are released during ex-
ercise and affect multiple organ systems via endocrine, para-
crine, and/or autocrine pathways (14). They are released from
skeletal muscle (myokines), brown adipose tissue (baptokines),
white adipose tissue (adipokines), neurons (neurokines), heart
(cardiokines), and liver (hepatokines). This review explores
how exerkines, via molecular signals and pathways, may ame-
liorate and/or attenuate the effects of COVID-19 and long
COVID on organ systems. This will highlight how and why ex-
ercise is the most important medicine and an effective treatment
for COVID-19, and especially for long COVID.
Organ Systems Affected by COVID-19/Long COVID and
the Effect of Exercise
The Cardiovascular System, COVID-19, Long COVID, and
the Effect of Exercise
Dysregulation of the renin-angiotensin-aldosterone system
(RAAS) has been a characteristic feature in COVID-19 (2).
This system is involved in the maintenance of electrolyte bal-
ance, vascular resistance, and thus maintenance of systemic
blood pressure and cardiovascular health (15). The dysregula-
tion may cause increased incidences of thromboembolism and
hypertensive episodes. The inflammation caused in the coro-
nary arteries during COVID-19 infection may speed up the
EXERCISE IS MEDICINE
1
Department of Exercise Science and Sports Medicine, Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, South Africa;
2
Division of Sports & Exercise Medicine, Department of Family Medicine &
Primary Care, School of Clinical Medicine, Faculty of Health Sciences,
University of the Witwatersrand, Johannesburg, South Africa; and
3
Wits
Sport and Health (WiSH), School of Clinical Medicine, Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Address for correspondence: Georgia Torres, PhD, Department of Exercise
Science and Sports Medicine, Faculty of Health Sciences, University of the
Witwatersrand, Johannesburg, South Africa; E-mail: georgia.torres@wits.ac.za.
1537-890X/2208/284–289
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formation of plaques and thus cause ischemic changes in the
heart (16). Electrolyte imbalance induced by the RAAS dysreg-
ulation also may lead to heart ailments seen with COVID-19
(e.g., hypokalemia can cause hyperpolarization of the cardiac
myocytes leading to arrhythmia) (17). The hypokalemia in
COVID-19 may also be caused by direct viral-mediated myo-
cardial injury leading to decreased cardiac output (18). In long
COVID, the immune-mediated inflammatory response is as-
sociated with endothelial dysfunction and thus increased risk
of deep vein thrombosis, pulmonary embolism, and bleeding
events (19). A reduction in vascular density also has been
found in patients with long COVID (20).
It is well established that exercise reduces the risk of cardio-
metabolic disease and mortality (21,22). The beneficial effects
of exercise on cardiovascular risk factors alone however, do
not account for the effects of exercise on cardiometabolic health
(14). The effect of exerkines on the cardiovascular system could
further explain how exercise is a medicine for this body system.
The exerkines, angiopoietin 1(myokine), fractalkine (myokine);
12,13 dihydroxy-9Z-octadecenoic acid (12,13 diHOME)
(baptokine), fibroblast growth factor 21 (FGF21) (hepatokine
and adipokine), IL-6 (myokine), IL-8 (myokine), musclin
(myokine and neurokine), myonectin (myokine), nitric oxide,
and vascular endothelial growth factor (VEGF) (myokines),
enhance vascularization, angiogenesis, endothelial function,
and myocardial energy utilization, thus mitigating the effects
of COVID-19 on the cardiovascular system (14). Exercise
has an anti-inflammatory effect (as is described in section 5),
which also may oppose the systemic inflammation that occurs
with COVID-19 and injures heart tissue.
In addition, the release of the muscle-derived mesenchymal stem
cells during exercise has been purported to repair cardiomyocytes
(23).This mechanism may be important when heart tissue has
been damaged with COVID-19 infection or long COVID.
The Respiratory System, COVID-19, and the Effect
of Exercise
COVID-19 can result in chronic health issues, such as im-
paired lung function, reduced exercise performance, and di-
minished quality of life. Pulmonary rehabilitation (PR) pro-
grams, including telerehabilitation programs, can be safe and
effective in improving respiratory symptoms and exercise ca-
pacity in patients with COVID-19, both during the acute
phase and in the postacute phase. Studies on the longer-term
implications of COVID-19 have emerged, and data suggest
that patients may experience prolonged symptom profiles, with
recovery only 29% at 5 months posthospitalization (24,25). At
6 months, impaired reduced pulmonary diffusing capacity per-
sists in 30% to 55% of patients, with evidence of evolving fi-
brosis (26). Studies have shown that PR can improve outcomes
in both acute and chronic COVID-19 patients, with significant
improvements in dyspnea, exercise capacity, and lung function.
A review highlighted the potential benefits of PR for patients
with preexisting pulmonary conditions and are recovering from
COVID-19 (27). Pulmonary rehabilitation should be consid-
ered as a key component of the management of COVID-19-
related respiratory symptoms. Energy conservation techniques
may play a pragmatic role in PR in mild to moderately severe
cases to counter post-COVID-19 fatigue (27).
While the COVID-19 virus primarily enters the body
through the upper respiratory tract, it is still not completely
clear which cells and tissues are initially targeted by the virus.
However, there is evidence to suggest that the virus can infect
and replicate in cells throughout the respiratory tract, includ-
ing in the upper and lower airways.
The mucosal immune system in the upper respiratory tract
plays an important role in defending against viral infections like
COVID-19. Increasing aerobic capacity can enhance immunity
through immune cells and immunoglobulins advancement and
regulating CRP levels (28). It could act as an antibiotic and anti-
oxidant, restoring normal lung tissue elasticity and strength (28).
Exercise has been shown to increase the levels and function
of immune cells like T-lymphocytes, neutrophils, macro-
phages, and monocytes, as well as increase the levels of immu-
noglobulins like IgA, which play a vital role in fighting lung in-
fections (29,30). Secretory IgA, in particular, is an antibody
that helps to neutralize viruses and prevent them from entering
cells. Further, exercise can potentially enhance the production
of secretory IgA in the respiratory tract (31). Exercise duration
may play a protective role in the respiratory tract through dis-
criminatory change in mucosal immunity through the cellular-
ity, antiviral activity, and gene expression (32).
A study that assessed whether exercise-induced myokines
would mitigate the COVID-19 infectivity of the bronchial ep-
ithelium through angiotensin-converting enzyme 2 -ACE2 in-
tonation demonstrated evidence suggesting exercise has a pro-
tective effect against COVID-19 (33).
The role of extracellular superoxide dismutase (EcSOD)
(myokine) in protecting against oxidative stress-related diseases
such as acute lung injury/acute respiratory distress syndrome
(ALI/ARDS) has been demonstrated (34). The dysregulation
and recruitment of activated neutrophils in the lung microvascu-
lature, interstitial, and alveolar space is a key step in ALI/ARDS,
leading to increased reactive oxygen species (ROS) and pro-
inflammatory mediators. EcSOD plays a critical role in the
first line of defense against superoxide generation in the lung
tissue. Studies have shown that reduced levels of EcSOD are
associated with disease development, while enhanced EcSOD
expression is protective against ROS and oxidative damage in
various pathological processes. Exercise-induced EcSOD has
been suggested as an effective therapeutic intervention for pre-
vention and treatment of numerous oxidative stress-related
diseases, including ALI/ARDS (34). The evidence supports that
exercise enhances immunity, antioxidative effects, function,
and overall benefits for the respiratory system in COVID-19.
The Neuroendocrine, Nervous System, COVID-19, Long
COVID, and the Effect of Exercise
The neurological consequences of COVID-19 infection in-
clude mild symptoms like headache, nausea, vomiting, dizziness,
loss of senses (smell and taste), and severe symptoms like ataxia,
convulsions, altered consciousness, ischemic or hemorrhagic
stroke, meningitis, encephalitis, rarely Guillain-Barré syndrome
variants, and new onset of psychotic symptoms (2). Autopsy
studies in COVID-19 deceased also have shown widespread
brain lesions (2). The impact of long COVID on the neurologi-
cal system includes tinnitus, hearing loss, vertigo, dysautonomia,
chronic fatigue syndrome, neuroinflammation, reduced cere-
bral blood flow, and small fiber neuropathy (3). It is suggested
that neurological symptoms arise due to the direct neuropathic
effect of the virus or the indirect effect of cytokine-induced
neuroinflammation (2).
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The exerkines apelin (adipokine and myokine), cathepsin B
(myokine), FGF21 (hepatokine and adipokine), irisin (myokine),
IL-6 (myokine), lactate (myokine), adiponectin (adipokine), and
GPLD1 (myokine) released during an exercise session increase
production of brain-derived neurotropic factor that enhances
neurogenesis, improve cognition and mood and increases syn-
aptic plasticity (14). These exerkines may thus be part of the
medicine needed for COVID-19 as they oppose the effects of
the virus. Furthermore, IL-6 increases both basal glucose up-
take and glucose transporter (GLUT4) translocation. In addi-
tion, IL-6 increases insulin-stimulated glucose uptake (23).
Thus, this exerkine may mitigate the detrimental effects of
COVID-19 on glycemic control.
A recent review on neuroendocrine symptoms of COVID-19
hypothesized that exercise attenuates β-cell dysfunction and the
long-term neuroendocrine effects of COVID-19 by moderating
the inflammatory response, supporting brain homeostasis, and
promoting insulin sensitivity (35). Long COVID also has been
associated with increased stress levels, anxiety, and depression
(35). Regular exercise has been shown to alleviate stress and
anxiety (36) and has been associated with lower odds of inci-
dent depression or an increase in subclinical symptoms (37).
The evidence indicates that exercise is an important medicine
for treating these symptoms of long COVID. In summary, exer-
cise remains a type of polypill that helps to ameliorate the harm-
ful effects of COVID-19 on the neuroendocrine system (23).
Organ Damage, COVID-19, and the Effect of Exercise
Multiorgan damage (to heart, lungs, liver, kidneys, pan-
creas, and spleen) has been associated with COVID-19 (3).
Mesenchymal stem cells released during exercise can repair
damaged myocardium and skeletal muscle tissue (23). In addi-
tion, circulating angiogenic cells released during exercise from
bone marrow mediate endothelial repair and angiogenesis.
These mechanisms may help repair the tissue damage that
the COVID-19 virus produces. Exercise also has been shown
to generate new cardiomyocytes, which would be beneficial
in the healing of damaged myocardium (38).
It also is important for damaged/nonfunctioning cells/organelles
(as can occur with COVID-19 infection) to be removed so that
body systems may function optimally. Exercise may help this
process since autophagy occurs with every exercise session,
within the heart (39), pancreas, liver, adipose tissue, brain,
and skeletal muscle (23). Noteworthy for COVID-19 rehabil-
itation is that research has identified that mitochondria are
damaged with COVID-19 infection and are involved in symp-
toms (such as fatigue) of long COVID (40). Exercise has been
found to “clean-up”nonfunctioning, damaged mitochondria,
and thus ensure that energy production is optimized and skel-
etal muscle health is maintained (41).
In addition, CD8+ and CD4+ T cells infiltrate injured skeletal
muscle tissue. Regulatory T cells migrate toward IL-33 and aid in
muscle regeneration by producing factors, such as amphiregulin,
that promote muscle stem cell proliferation (42).
Immunity, COVID-19, Long COVID Response, and the Role
of Exercise, Including Exercise as an Immune Adjuvant
A subthreshold and delayed protective T cell-mediated adap-
tive immune response in symptomatic patients is pronounced
in patients with severe COVID-19 in the initial period (2).
Figure: COVID-19 infection versus exercise effects.
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Immune dysregulation has been reported in individuals with
long COVID. This involved exhausted T cells, reduced or ab-
sent CD4
+
and CD8
+
T-cell numbers (43) and a lack of naïve
T and B cells (44,45). In addition, T-cell senescence becomes
an issue in the elderly, and this is a population that is at risk
of severe outcomes with COVID-19 infection. With increasing
age, decreased numbers of new, naïve T cells are released from
the thymus, and the ability of the adaptive immune system to
respond to novel pathogens (like COVID-19) declines (42).
Exercise has been shownto release the myokines IL-6, IL-7,
and IL-15 that specifically increase recent thymic emigrant
T-cell output from the Thymus, and promote the survival
and increase the proliferation of naïve T cells (46,47). This
may protect T cells from the effects of COVID-19 infection
and outputs. In addition, T cells and B cells are mobilized into
the blood circulation by the increase in catecholamines during
exercise and at exercise cessation the myokines are proposed
to affect immune cell redistribution and activation (48). The
immune dysregulation and lack of response that occurs with
long COVID infection, may thus be attenuated by effects of
exercise on immunity.
Furthermore, the frequent redistribution of natural killer
(NK) cells and viral-specific T (VST) cells with each exercise
bout increases immune surveillance and reduces the accumu-
lation of senescent/exhausted T cells, while maintaining the
number and diversity of naïve T cells. In turn, this reduces in-
fection risk, increases the manufacture of therapeutic VST
cells specific to latent and nonlatent viruses and increases pro-
tection provided from vaccines (46,49).
Lastly, aerobic exercise has been shown to preferentially
mobilize lymphocytes with effector functions (i.e., NK cells,
CD8+, CD4+ T cells, and γδ T cells) (50). As previously men-
tioned, these are the same Tcells that have a reduced or absent
response during COVID-19 infection. Could exercise be a
medicine for counteracting this negative effect of COVID-19?
Initial inflammation during COVID-19 infection causes the
release of pro-inflammatory cytokines (IL-6, TNF-a) (2,51)
and recruitment of peripheral immune cells. This induces more
tissue injury and in severe cases, leads to cytokine storm that con-
sequently kills T cells and delayed/or suppressed B cell-mediated
humoral response (2). Exercise can reduce this inflammation via
the action of IL-6, which when released as a myokine during ex-
ercise, has anti-inflammatory actions via the induction of IL-10
and IL-1RA by monocyte/macrophages (46). IL-6 released
during exercise also inhibits the action of pro-inflammatory cyto-
kinessuchasCRP,TNF-alphaandserumamyloidA(SAA),
even in the elderly (42). Exercise may help reduce chronic in-
flammation (that occurs with long COVID), as a result of IL-6
(myokine) enhancing lipolysis and fat oxidation (reducing vis-
ceral fat), via a mechanism that involves AMPK activation (52).
Reducing adiposity may be beneficial to attenuating the ef-
fects of COVID-19, as circulating adipokine levels have been
associated with COVID-19 hospitalization, but not mortality
(53). Although vigorous exercise may induce short-term in-
flammatory effects, the overall effect of a moderate intensity ex-
ercise bout, is anti-inflammatory (42). Lastly, a review found
that increasing the aerobic capacity (CRF) could produce im-
provements in the function of immune and respiratory systems,
particularly specific to COVID-19 infections (28). Therefore,
exercise is an important medicine for the immune system during
COVID-19 and for long COVID as it maintains/improves
immune function, prevents immune senescence, reduces in-
flammation, mobilizes, and redistributes virus-specific T cells,
and reduces stress.
As a species, our origins as hunter-gatherers necessitated
covering large distances using multiple muscle groups daily in
the pursuit of food and water to survive (54). Challenging nat-
ural environments, the accompanying physical demands and
resultant natural selection forged our modern-day genome
(55). Being physically active was necessary for survival. In a
modern-day context, the benefits of regular physical activity
in promoting cardiovascular health (and with it survival) has
been widespread for some time (56,57). The effects of physical
activity on the immune system have more recently been well de-
scribed (58) and brought to the forefront by recent research re-
lated to COVID-19 outcomes (4,7,9) and vaccine efficacy (59).
In a recent systematic review and meta-analysis, Chastin et al.
(60) quantified the reduction in community-acquired infections
associated with habitual physical activity as 31% with a 37%
reduction in mortality. Physical activity resulted in increased
CD4
+
counts, greater concentrations of salivary IgA and de-
creased neutrophil counts compared with controls. Physical ac-
tivity also was associated with higher antibody responses to
vaccination (60).
Interest in the potential impact of physical activity on vaccine ef-
fectiveness also was piqued by the COVID-19 epidemic as it be-
came apparent that vaccines were a powerful tool in lowering
morbidity and mortality (61). Previous cross-sectional studies
and randomized controlled trials have demonstrated increased
postvaccination antibody titer levels in adults who engage in
regular physical activity (62,63). This effect appears tobe par-
ticularly beneficial in the elderly (64). In the first study that
used objectively-measured physical activity data, Collie et al.,
showed enhanced effectiveness of vaccination with Ad26.COV2.S
(Janssen/J&J) against COVID-19 hospital admission (59). The
study also suggested a possible dose-response.
Conclusion
The Figure compares the effects of COVID-19 versus the
“opposing”effects of exercise to this virus. The evidence pre-
sented in this review adds to the Nieman et al. (65) viewpoint,
that it is time to include “treatment for and reduced risk of
COVID-19 and long COVID”to the “Exercise is Medicine list
of physical activity-related health benefits.”The potent,
multi-organ effects of exerkines position exercise as the most
important medicine for COVID-19 and long COVID. How-
ever, it should be noted that the evidence exists for non-
COVID-19 patients and needs to be verified in COVID-19
and long COVID patients.
Future research needs to investigate the suggested molecu-
lar pathways and mechanisms within clinical trials of exercise
interventions for long COVID. This will allow for the map-
ping of molecular transducers and signaling pathways that
occur during exercise with individuals post COVID-19, with
long COVID.
The authorsdeclare no conflict of interest and do not have
any financial disclosures.
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