ARTICLE

Exercise Is Medicine in Cystic Fibrosis

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Courtney M. Wheatley 1, Brad W. Wilkins 2, and Eric M. Snyder 1

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1
Department of Pharmacy Practice and Science, University of Arizona, Tucson, AZ; and 2Nike Sport Research
Laboratory, Nike Inc., Beaverton, OR

WHEATLEY, C.M., B.W. WILKINS, and E.M. SNYDER. Exercise is medicine in cystic fibrosis. Exerc. Sport Sci. Rev., Vol. 39,
No. 3, pp. 155Y160, 2011. Exercise activates adrenergic and purinergic pathways that regulate activity of ion channels on airway epithelia
cells and sweat glands. Therefore, we hypothesize that exercise is not only an important therapy for cystic fibrosis (CF) patients by facilitating
systemic improvements but, more importantly, that exercise can improve the pathophysiological ion dysregulation at a cellular level, thereby
enhancing quality of life in CF. Key Words: airway surface liquid, sweat gland, CFTR, ENaC, ADBR2, P2Y2, thermoregulation

INTRODUCTION CFTR in plasma membranes. This altered sweat gland func-

Cystic fibrosis (CF) is one of the most common lethal
genetic diseases in white patients, affecting nearly 30,000
individuals in the United States. Approximately 4% of white
individuals carry one mutation of the CF transmembrane
conductance regulator (CFTR) gene. The pathological con-
sequences of this mutation can impinge function of the
reproductive, digestive, and respiratory systems, as well as
temperature regulation and fluid balance. Although CF is a
multisystem disease, lung disease results in 85% of CF mor-
tality, according to the CF Foundation Patient Registry. As
an autosomal recessive disease, an individual with CF inherits
a CFTR mutation on both their paternal and maternal alleles.
Thus, the defective CFTR protein that is produced results in
improper ion transport because of production of a nonfunc-
tional or mislocalized CFTR chloride (Clj) channel on the
apical membrane of epithelial cells. In the lung, this mutated
CFTR leads to decreased Clj secretion and hyperabsorption
of sodium (Na+) through epithelial Na+ channels (ENaC)
(23). Consequently, in the CF lung, airway surface liquid
(ASL) depth and mucociliary clearance are reduced, leading
to airway obstruction, infection, and inflammation. Addi-
tionally, at the sweat gland, CFTR dysfunction leads to both
high rates of sweat secretion and excessive loss of both Na+
and Clj. In contrast to the lungs, hypoabsorption of Na+
by ENaC in sweat gland ducts is linked to the lack of
Address for correspondence: Eric M. Snyder, Ph.D., Department of Pharmacy Practice
and Science, University of Arizona, 1703 E. Mabel, Tucson, AZ 85721
(E-mail: snyder@pharmacy.arizona.edu).
Accepted for publication: February 14, 2011.
Associate Editor: Stephen M. Roth, Ph.D., FACSM
0091-6331/3903/155Y160
Exercise and Sport Sciences Reviews
Copyright * 2011 by the American College of Sports Medicine
tion can lead to dehydration, hyponatremia, and hypochlor-
emia in patients with CF especially during exercise in the
heat (4,21,22).
Exercise can provide improvements to quality of life in CF
patients, with benefits including increased exercise tolerance
(20), increased respiratory muscle endurance (20), reduced
residual volume (3), increased sputum expectoration (25),
and reduced rate of decline in pulmonary function (27). It
also has been demonstrated that high levels of aerobic fitness
in CF patients are associated with a significantly lower risk of
death (19). In addition, exercise training is known to im-
prove fluid balance and retention of serum electrolytes in
healthy individuals, likely through the plasma volume ex-
pansion that is characteristic of exercise and possibly through
a direct effect on ion regulation in the sweat glands them-
selves. Therefore, exercise training has the potential to im-
prove the fluid and salt loss due to sweat gland dysfunction in
CF patients by reducing thermal strain and the incidence of
dehydration, possibly through direct interaction of CFTR-
related mechanisms. In this review, we will first present the
previous work that has led to the belief that exercise is a
vital component of the therapy regimen prescribed to CF
patients because of the multitudinous systemic benefits. We
will then present the emerging data and our recent research
supporting the mechanisms by which exercise is medicine for
CF patients at a cellular level by promoting improvements in
ion balance by acting directly on sweat glands and airway
epithelia to improve ion dysregulation and thereby enhance
pulmonary function, quality of life, and life expectancy.
EXERCISE IN CF
The ideal therapy in CF lung disease is one that demon-
strates an attenuation of the characteristic 2%Y3% annual

155

Copyright © 2011 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 decline in pulmonary function and forced expiratory volume
in 1 s (FEV1) and facilitates an improvement in salt trans-
port. Previous research demonstrated that CF patients with
a maximal oxygen consumption (V̇O2peak) greater than 82%
of their predicted value had an 83% 8-yr survival rate com-
pared with only a 28% 8-yr survival rate for patients with a
V̇O2peak percent predicted less than 58%. Additionally, this
study found that aerobic fitness was an independent predictor
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of 8-yr survival, whereas FEV1, the gold standard for the
assessment of disease progression and life expectancy, was not
(19). Exercise tolerance, aerobic capacity, and respiratory
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muscle endurance all were significantly increased in a study
of subjects completing a 3-month supervised running pro-
gram. Unlike subjects in the control group, subjects who
completed the running program demonstrated no significant
decline in pulmonary function (20). These findings were
confirmed in another study, which demonstrated similar im-
provement in V̇O2peak, work capacity, forced vital capacity
(FVC), amount of time spent in vigorous physical activity,
and perceived health using a 6-month partially supervised
conditioning program (15). Although less effective when
compared with chest physiotherapy, exercise tended to in-
crease mean daily sputum expectoration weight 24 T 25 at
baseline versus 37 T 47 g post-2-month training program (25).
These advantageous systemic changes in response to exercise
demonstrate a better quality of life and suggest increased life
expectancy for CF patients who exercise, but there is limited
mechanistic data on the effects of exercise on providing im-
provements to ion regulation at the cellular level in vivo in
CF. We hypothesize that exercise can be beneficial to patients
with CF at a cellular level by both increasing Clj secretion
and inhibiting Na+ hyperabsorption across airway and alve-
olar epithelial cells, thereby ameliorating ion dysregulation
in the CF lung, and also by improving thermoregulation and
fluid balance through plasma volume expansion and/or a direct
effect on the sweat glands.
Ion Regulation in the Sweat Glands
Along the reabsorptive duct of the sweat gland, CFTR is
essential for Clj absorption (30). Indirectly, malfunctioning
CFTR and the lack of Clj absorption also lead to a limitation
in Na+ absorption via ENaC in sweat gland ducts (24). This
ion dysregulation in the sweat glands of CF patients results
in abnormally high Na+ and Clj concentration in secreted
sweat, and since this was discovered by Di Sant’Agnese et al.
(13), it has become a diagnostic characteristic of CF. Exercise
training activates pathways to mediate alterations in the ion
composition of sweat in healthy subjects. Normal sweat secre-
tion can be controlled by both A-adrenergic (ADBR2) recep-
tors and cholinergic mechanisms. However, sweat glands in CF
patients lack any ADBR2-stimulated sweat production because
ADBR2 sweat secretion is mediated through CFTR (26).
However, cholinergic sweat secretion is dependent on both
calcium-dependent potassium channels and CFTR (26). The
significantly elevated sweat production and sweat salt content
during exercise in patients with CF is primarily related to the
cholinergic activation of eccrine sweat glands. An interesting
finding from studies of ADBR2-mediated sweat rate demon-
strated that ADBR2-mediated sweating in healthy CF carriers
is essentially half that of healthy controls. These researchers
156 Exercise and Sport Sciences Reviews
Copyright © 2011 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
concluded that CF carriers generally have an ADBR2-stimu-
lated sweat secretion that is significantly reduced compared
with their healthy counterparts (5). If a functional CFTR is
necessary for normal Clj absorption, these findings suggest
that even CF carriers may have altered, or reduced, CFTR
expression in the sweat gland.
Thermoregulation and Fluid Balance
Previous work has demonstrated heat intolerance in chil-
dren and adults with CF (13,22). Orenstein et al. (21)
reported high sweat rates and substantially higher concen-
trations of both Na+ and Clj in sweat of patients with CF.
Thus, the most common underlying factors associated with
this heat intolerance with CF are dehydration, hypochlor-
emia, and/or hyponatremia (4). This suggests that during ex-
posure to high environmental heat, patients with CF may
endure significantly elevated thermal and possibly cardiovas-
cular strain. Exploiting the known training adaptations,
including plasma volume expansion and serum electrolyte
retention, individuals with CF may be able to take advantage
of a protective effect of chronic exercise.
Plasma volume expansion is a clear adaptation of exercise
training and heat acclimation in humans with normal sweat
and ion production. This plasma volume expansion may be
an important mechanism for the adaptations to heat accli-
mation, including sweat dilution and a reduction in sweat
Na+ and Clj concentration, which would be a particularly
important adaptation for patients with CF (1,16). The ques-
tion of whether plasma volume expansion occurs in CF re-
mains unanswered. Recent work demonstrating that baseline
plasma vasopressin levels were significantly elevated in non-
CF ‘‘salty sweaters’’ and tended to be higher in CF patients
when compared with healthy controls and finding a positive
relationship between sweat Na+ concentration and plasma
vasopressin concentration support the hypothesis that plasma
volume expansion may indeed be a natural adaptation to salty
sweat (8). More dilute sweat with heat acclimation acts to
retain serum Na+ and Clj during subsequent heat exposure
(6,22). In addition to sweat dilution, exercise training and
acclimation to heat reduces the core temperature threshold
for reflex vasodilation and sweating, thereby maximizing
evaporative heat loss and decreasing thermal strain (18). In
addition, acute plasma volume expansion reduces heart rate
and increases stroke volume during heat stress, thereby de-
creasing cardiovascular strain for any given rise in core body
temperature (29,35). In general, the physiological adaptations
from exercise training and acclimation to heat act to decrease
cardiovascular and thermal strain during subsequent heat
exposure.
To our knowledge, only one study has examined physio-
logical adaptations to heat acclimation, per se, in CF patients.
Orenstein et al. (22) reported that subjects with CF tolerated
repeated heat exposure (8 d of combined exercise and heat)
remarkably well, and core temperature during exercise in the
heat decreased after acclimation in subjects with CF. How-
ever, combined exercise and heat acclimation failed to de-
crease sweat Na+ and Clj concentrations in patients with
CF. As a consequence, serum Na+ and Clj concentrations
remained depressed in CF. Unfortunately, this study did not
investigate potential adaptations in skin blood flow regulation
www.acsm-essr.org
 or sudomotor control of sweating, which may have contrib-
uted to the enhanced heat tolerance after exercise and heat
acclimation in these CF patients. Skin blood flow responses
to local and passive whole body heating, and muscle blood
flow response during exercise, seem normal in CF (28,34).
Thus, improvements in reflex cutaneous vasodilation after
exercise training are likely in patients with CF. The mecha-
nisms responsible for the normal enhanced absorption of salt
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in the sweat gland adaptation after exercise training are not
well understood. Because Orenstein et al. did not observe
more dilute sweat (enhanced absorption) in CF after combined
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exercise and heat acclimation, the mechanism may be related
to the function of CFTR and ENaC in the sweat gland.
The high sweat rate and high concentrations of Na+ and
j
Cl in the sweat may significantly reduce serum osmolality.
The low osmolality in body fluids may deprive individuals
with CF of a thirst stimulus, further exacerbating dehydration
during combined exercise and heat stress. An important con-
sideration when using exercise as medicine in patients with
CF is fluid and electrolyte replacement (4). Unfortunately,
replacement strategies specifically have not been identified
in CF. Recent work has demonstrated that the serum salt and
osmolality increased less in response to dehydration but that
there was a greater relative loss of plasma volume in CF
patients. There was no difference in thirst perception, but CF
subjects drank approximately 30% less, leading the researchers
to hypothesize that there may be negative feedback triggering
slowed voluntary drinking and that thirst-guided fluid re-
placement, rather than forced drinking, may be most appro-
priate to effectively maintain body weight and decrease
recovery heart rate after exercise (7).
Ion Regulation in the Lung
Epithelial cells of the bronchial tree and alveoli are cov-
ered in a surface liquid composed of mucus, ions, inflamma-
tory proteins, and water. Airway surface liquid is a fundamental
component of the pulmonary defense and one that has been
shown to influence overall pulmonary function, where ho-
meostasis is achieved by keeping the lungs moist but not
overly wet. Maintaining ASL depth, normally approximately
7 Km, allows for effective ciliary beating to facilitate effec-
tive mucus clearance and prevent mucus plugging that can
limit gas transfer. Maintaining the ideal hydration of the air-
way lumen and alveoli is achieved by the active transport
of salt prompting the subsequent osmotic water flux. The
absorptive pathway for removal of excess fluid is mediated
through ENaC, which moves Na+ down its concentration
gradient into the cell where it is then pumped out on the
basolateral side, by Na+/K+-ATPase, maintaining this in-
ward electrochemical gradient. To maintain electroneutrality,
negatively charged Clj will move paracellularly through the
‘‘loose’’ tight junctions to balance the positively charged Na+
influx. In the alternative, Clj can be secreted from the airway
epithelia primarily through CFTR and also, to a lesser extent,
by calcium-dependent chloride channels (CaCC), with Na+
balancing this anion efflux through paracellular transport
allowing for an increase in ASL depth. The outward concen-
tration gradient for this efflux of Clj is facilitated through
the activity of the basolateral Na+/K+/2Clj cotransporter.
It is the regulation of these channels to control the net ion
Volume 39 & Number 3 & July 2011
Copyright © 2011 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
transport and salt load that maintains homeostasis of ASL
depth (11).
During exercise, two pathways for regulating ion compo-
sition of ASL are initiated, both of which could have favor-
able effects on ion regulation in CF. This has led us to our
emerging hypothesis that exercise is beneficial, beyond the
systemic improvements mentioned previously, at a cellular
level by helping to keep the lungs moist through amelioration
of ion dysregulation that is a hallmark of this disease. Exercise
results in endogenous stimulation of ADBR2 by elevated epi-
nephrine (Epi) and stimulation of purinergic (P2Y2) receptors
by adenosine triphosphate (ATP) and adenosine (ADO) (11).
Moderate exercise, greater than 50% maximal oxygen con-
sumption, markedly increases catecholamine (norepinephrine
(NE) and Epi) levels. As a G-protein coupled receptor, bind-
ing of Epi to ADBR2s causes release of the Gs> subunit, which
then activates adenylate cyclase, allowing for conversion of
ATP to cyclicYADO monophosphate (cAMP). cAMP can
then mediate the activation of protein kinase A (PKA).
Phosphorylation of the regulatory domain of CFTR by PKA
causes channel activation, resulting in Clj efflux to the apical
side of airway epithelial cells. A-agonist stimulation has dem-
onstrated an increase in Clj secretion toward the lumen across
the canine trachea, in vitro (17). When both ENaC and CFTR
are expressed, cAMP agonists decrease ENaC activity because
of the inhibitory action of CFTR on ENaC; however, when
CFTR is absent, which occurs with the $F508 mutation,
which is present in 90% of CF patients, cAMP increases Na+
reabsorption, highlighting the important inhibitory role of
CFTR in restricting ENaC activity (11). In the second path-
way, ATP is released from airway epithelia in response to
mechanical stress that occurs with the increased ventilation of
exercise. Both ATP and its metabolite ADO can interact with
P2Y2 receptors on the apical membrane causing a depletion
in phosphatidylinositol 4,5-bisphosphate (PIP2). Because PIP2
is required for protein kinase C-mediated ENaC activation,
P2Y2 receptor activation thereby inhibits ENaC. Purinergic
receptor activation also can stimulate CaCC activity through
the concurrent inositol trisphosphate-mediated release of Ca+2
from endoplasmic reticulum calcium stores (11). Research has
shown that nucleotide application to the airway lumen medi-
ates ASL secretion in both healthy and CF airway epithelia
(9). Additionally, the ADO-2b (A2b) receptor also is present
on the apical membrane of the airway epithelia and increases
PKA to activate CFTR (9) (Fig. 1). Through these pathways,
it is clear that exercise could act to ameliorate ion dysregula-
tion in CF and provide benefits to CF patients.
Recent work in CF airway submucosal gland serous cells
has demonstrated that salmeterol, a long-acting A-agonist,
restores normal secretory function by stabilizing CFTR and
allowing for increased Clj secretion (12). Also, there has been
recent in vivo research demonstrating that exercise inhibits
ENaC function in both healthy and CF subjects. At rest, nasal
potential difference (NPD) was more negative in CF because
of the lack of Clj efflux and hyperabsorption of Na+ (negative
inward current). With exercise, NPD became less negative in
CF subjects so that, at the end of exercise, there was no dif-
ference in NPD between healthy and CF subjects (2,14). The
effect of amiloride on NPD also was reduced during exercise,
suggesting that exercise partially blocked ENaC conductance.
Exercise in CF 157
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Figure 1. Ion regulation in airway epithelial cells. Stimulation of the A2-adrenergic receptor (ADBR2) by A-agonist or catecholamines, primarily Epi, mediates
activation of adenylate cyclase (AC) by Gs>-subunit of the G-protein complex and downstream activation of protein kinase A (PKA); PKA then results in the
activation of the cystic fibrosis transmembrane conductance regulator (CFTR), epithelial Na+ channels (ENaC), and Na+/K+ ATPase to facilitate Na+ absorption
and Clj secretion. The CFTR activation also acts to inhibit ENaC activity to control Na+ reabsorption. Stimulation of the P2Y2 receptor by ATP or adenosine
(ADO) causes cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2). Because PIP2 mediates ENaC activation, the depletion of PIP2 thereby inhibits ENaC.
The production of inositol trisphosphate from PIP2 subsequently stimulates calcium-dependent chloride channels (CaCC) activity by causing the release of
Ca+2 from the endoplasmic reticulum. Additionally, the ADO-2b (A2b) receptor, when activated by ADO, increases PKA to subsequently activate CFTR.

These findings suggest that exercise-mediated inhibition of
ENaC and possible CaCC activation could help to increase
water content in the mucus, providing greater ease for expec-
toration (14). Because of the lack of functional CFTR in CF,
ADBR2-mediated stimulation has minimal effect on Clj se-
cretion; however, P2Y2 agonists ATP/ADO also are increased
during exercise, which can mediate inhibition of ENaC Na+
absorption and cause CaCC-mediated Clj efflux through a
CFTR-independent pathway (2).
Ameliorating Ion Dysregulation in the CF Lung
Quantitative analysis of ASL composition is extremely
difficult because of the layer’s thinness and limited accessi-
bility. Exhaled air, predominantly composed of water vapor,
also contains small droplets of fluid that are produced by
the shear force of turbulent flow upon exhalation across the
ASL. Therefore, the composition of one’s exhaled breath is
believed to be a surrogate, although diluted, marker of the
composition of the ASL from any location in the lung, in-
cluding the alveoli. The composition of the exhaled breath
condensate (EBC) then can be analyzed for solutes, including
ions (10). Our laboratory has been using ion composition of
EBC to understand composition of ASL noninvasively and
to study how different stimuli can alter this composition in
both healthy subjects (n = 26) and mild-to-moderate patients
with CF (n = 10, FEV1 = 70 T 24% pred, forced vital capacity
(FVC) = 85 T 20% pred) First, we have demonstrated that
the administration of the A-agonist albuterol alters EBC ion
composition, significantly increasing net exhaled Clj from
the baseline in healthy subjects and showing a trend of
reducing exhaled Na+ in both healthy and CF subjects
(Fig. 2). Net exhaled Clj was calculated as gross exhaled Clj
concentration plus the absolute value of the percent change
in exhaled Na+ from the baseline multiplied by the gross
exhaled Clj concentration, which we have used to account
for Clj influx that would follow Na+ absorption to maintain
electroneutrality. These results demonstrate that EBC com-
position is regulated because it can be altered by the admin-
istration of a A-agonist.
Second, we have shown that there is a negative relation-
ship between exhaled Na+ and gas diffusion at the individual
functional alveolar-capillary unit (alveolar-capillary membrane
conductance/pulmonary capillary blood volume). Where in-
creased exhaled Na+ could be indicating an increase in lung
water, which consequently could limit gas transfer (31). This
correlation between exhaled Na+ and gas transfer suggests
that a portion of EBC droplet formation is occurring in the
respiratory zone where gas diffusion takes place. Third, both
healthy and CF subjects with a more active ENaC genotype

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Figure 2. Exhaled breath condensate response to A-agonist. Exhaled
ion concentration in exhaled breath condensate at each time point col-
lected after A-agonist, albuterol, administration in healthy (white bars)
and cystic fibrosis (CF) subjects (black bars) (42% vs 20% female subjects;
age, 28 T 9 vs 25 T 8 yr, height, 173 T 11 vs 170 T 6 cm; weight, 71 T 13 vs
64 T 8 kg; BMI, 24 T 4 vs 22 T 3 kgImj2; healthy vs CF, respectively, mean T
SD). Top: gross exhaled Na+ concentration. Bottom: net Clj efflux (calcu-
lated as the gross Clj concentration corrected for the percent change in
exhaled Na+ from the baseline). The error bars represent the SE of the
sample mean. *P G 0.05, Dunnett test comparing all treatments to baseline.
†P G 0.05 healthy vs CF.
have lower exhaled Na+ levels (32). When we performed
maximal exercise tests with measurements of lung diffusion,
we found that membrane conductance was significantly lower
in the CF patients at rest, and the difference was augmented
with exercise. However, exercise did mediate an improve-
ment in lung function and lung diffusion, demonstrating an
increase of 37% in forced expiratory flow at 25%Y75% of
FVC (FEF25Y75) and 29% in membrane conductance in these
CF patients (33). These data demonstrate that exercise can
cause systemic benefits by improving gas transfer and mediat-
ing bronchodilation to a level that is similar to what can be
achieved with the administration of a A-agonist. Essentially,
these improvements in membrane conductance could be due
to exercise-mediated cellular improvements in ion regulation
to help moisten the lung and ameliorate some of the gas dif-
fusion limitations present at rest. The therapeutic benefits of
exercise, we hypothesize, stem from the idea that exercise could
Volume 39 & Number 3 & July 2011
Copyright © 2011 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
act similar to an exogenous agonist (drug therapy); with ex-
ercise, there is not only the ability to stimulate adrenergic-
mediated regulation of ions and lung fluid, but exercise also
facilitates the activation of purinergic mechanisms for main-
taining lung fluid homeostasis. It is this addition of the
purinergic stimulation of CFTR-independent Clj secretion
through CaCC and ENaC inhibition that may be the most
beneficial for ameliorating ion dysregulation in the CF lung.
CONCLUSIONS
Despite evidence that exercise improves the quality of life
in patients with CF, there is little mechanistic data avail-
able regarding the influence of exercise on ASL ion regula-
tion (i.e., evidence for what is occurring on a cellular level)
and mechanisms of thermoregulatory adaptations in this
population. Because of endogenous adrenergic and purinergic
ion channel regulation in the airway epithelial cells, it is
likely that exercise could attenuate CFTR dysfunction and
ENaC hyperactivity and additionally activate CaCC, ame-
liorating ion dysregulation in CF. Evidence of this exercise-
induced ion regulation in the lung could provide incentive
for CF subjects to implement and maintain the prescribed
exercise as medicine through childhood and adult life to
prevent the progression of pulmonary disease.
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