Chronic exercise training protects aged cardiac
muscle against hypoxia.
J Y Wei, … , W Grossman, D Mendelowitz
J Clin Invest.
To test the hypothesis that chronic exercise may improve tolerance to hypoxia in aged
hearts, we compared cardiac function of exercised rats to that of their age-matched,
nonexercised controls. Right ventricular papillary muscles were removed from young adult
(9 mo) and old (24-26 mo) male Fischer 344 rats that were chronically exercised on a rodent
treadmill and from their age-matched, nonexercised controls. During isometric contraction,
hypoxia depressed contraction and relaxation in all muscles, but to a lesser extent in the
exercised groups. A significant exercise effect was observed in the following variables: the
maximum developed tension, the maximum rate of tension development, the maximum rate
of tension decline, and the time required for the hypoxia to reduce maximum tension by
20%. The maximum rate of tension decline was more sensitive to hypoxia than was the
maximum rate of tension development in all groups. Exercise also had an effect on the
temperature dependence of cardiac performance during hypoxia. Thus, chronic exercise
results in the preservation of both contraction and relaxation during hypoxia for aged as well
as young adult hearts.
Find the latest version:
Chronic Exercise Training
Jeanne Y. Wei, Yun-XiaLi, Thomas Lincoln, William Grossman, and David Mendelowitz
CharlesA.DanaResearchInstituteandtheHarvard ThorndikeLaboratory ofBeth IsraelHospital, Department ofMedicine, Beth Israel Hospital and Harvard Medical School; and Geriatric Research Education and ClinicalCenter, West Roxbury/BrocktonVeterans Administration Medical Center, Boston, Massachusetts 02215
To test the
hypothesisthat chronic exercise may
compared cardiac function
of exercisedrats to
of their age-matched, nonexercised
papillary muscleswere removed
(9 mo)and old
(24-26 mo)male Fischer 344
rats that were
chronically exercised on a rodent treadmill and
from their age-matched, nonexercised controls.
isomet-ric contraction, hypoxia depressedcontraction and relaxation in
toa lesser extent
significant exercise effectwasobserved in the
tension, the maximumrate
required for the
by 20%. The maximumrate
of tension declinewas more
develop-ment in all groups.
Exercisealso had an
dependence of cardiac
during hypoxia. Thus,
chronic exercise results in the
of both contraction
during hypoxia for agedaswell as
Exercise conditioning ofyoung
capacityand tolerance to
change in aerobic energy
metabo-lism (1-3). The lack of changein
sarcoplasmic reticular calcium transport, and the
activity (3, 4) may be due to the
high intrinsic aerobic reserve in the young (1-5). With
advanc-ingage both the heart's
metabolism may be reversed by exercise conditioning (1, 6,
1-13). However, it has notbeen
established whether chronic
hypoxia in the aged heart.
Since relaxation ismore
(14), and since relaxation is enhanced by exercise training in old rats
postulated that chronic exercisewill protect the
aged cardiac muscle against hypoxia.
Address correspondence to Dr. J. Wei, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215.
Receivedfor publication 10 September 1986 and in revised form 8 August 1988.
treadmill exercise regimenwas
imposedon adult male Fischer 344 rats,amammalian model ofaging that is free of atherosclerosis and hypertension (15). Because differ-ent results concerning the effect ofhypoxia on myocardial
relaxation have beenreported from studies conducted at dif-ferent temperatures (16), we chose to perform this study at three
temperatures.The left ventricle
(6, 8, 10-13),andexercise
condi-tioning alters cardiac functionin
theyaresenescent or not(13, 17). Therefore, it would be diffi-cult to separate the effect of training on hypertrophied myo-cardium from its effect on
aged myocardiumper se when
performance (13). Consequently,to
minimize confounding factorswe chose to measure
which does not show significant age-related hypertrophy in the
(6, 8, 10, 13). Finally, young adult rats were also studied to
determine the effectsnot
only of chronic exercise but also of
myocardial toleranceto hypoxia.
Animal selection and exercise
Young adultandold maleFischer 344rats wereobtained from Charles River BreedingLaboratories(Wilmington, MA) orHarlan Sprague Dawley,Inc.(Indianapolis,IN).Atthestartof thestudy,thetwoage groups were aged 4.5 and 21 mo, respectively, and 9 and 25 mo, respectively,atthe endof the study. The males of thiscolonyshowa
50%mortalityat24 mo, whethertheyareexercisedor not(seebelow). The rats werehoused in the Animal Quartersof the Beth Israel Hospital(Boston,MA)at23±1VCon a12-hlight/dark cycleandwere
fed PurinaRatChow and tapwateradlib.Atinitiation ofthestudythe
ratsbecame acclimatedtothepersonnel and exercise equipment by walkingon aslowlymovingrodenttreadmill for 5-10 min each day for 3 d(12). Gentle mechanicalproddingand verbalconversationat
nor-malintensitywereusedtoencourage continuousrunningin therats.
After initiation the rats ran 5 d/wk on amotor-driven rodent treadmill for 20wk.Theangle of inclinewas00 throughoutthe
exer-cisetrainingprogram for both ages. Thetraining protocolwasdesigned
toexercise the aged animalsatapproximatelythesamepercentage of maximalaerobic capacityasthe youngadultgroup(13, 18, 19).
Ac-cordingly, the treadmill speeds and exercise durations were selected to exercise the animals of both groupsat - 55-65% maximal aerobic capacity(1.2 km/h for 60 min in young adult rats, 0.9 km/h for 30 min in aged rats). Two age-matched sedentarycontrolgroups ofratswere handledsimilarlyandplacedonthenonmoving treadmill for thesame
length of timeastheexercise groups.
1.Abbreviations usedinthis paper: DT, developedtension; dT/dt,rate
of tension development; -dT/dt,rateof tensiondecline; (dT/dt,,)/ DT, maximum rate of tension development normalized for DT;
(-dT/dtma,)/DT,maximum rate of tension decline normalized for DT;
Lma,lengthatwhich thedeveloped isometric tension ismaximal; LV, left
778 J. Y. Wei, Y.-X.Li, T.Lincoln, W.Grossman, andD.Mendelowitz J.Clin.Invest.
© The AmericanSocietyfor ClinicalInvestigation,Inc.
At the start the animalswereassigned to the control or the exercise groupinalternating sequence. Because the males of this rat colony show a50%o mortalityat24 mo, and substantialprior experience from our laboratory has shown that - 10%oftheyoung adultand60%of
the oldanimals usually failto runsatisfactorily, nearlythreetimesas
many old rats as young adult rats were initially included in the study cohort. For every oldratassignedtothe control group(n=16),twoold rats were assigned to the exercise group (n = 32). Of the animals assigned to the exercise group, 18 old animals andIyounganimal did not runsatisfactorily. They were not placedintothe controlgroup but wereomitted from the study. Previous studies have shown that the animals that refusetorundonotdiffer from those that dorunwith regardstobodyweight, heartweight,ormusclefunction (I 1).
Duringthecourseof the exerciseprotocol, onlyoneyoungadultrat
(a control) died. As expected, mortalitywashigher among the old animals. 8of the 16 control and7of the 14 exercisedratsdied before completion of the study. Themortalityratesanddates of deathwere
similar between the old exercise andold control groups. The body weight, bloodpressure, and activity levels were not different between theanimals thatdied and their age-matched survivors. No acute changes in these parameterswerenotedbeforeananimal's death, and thedistribution ofmortalityovertimewas notdifferent between the old exercise and old control groups.
Atthe endof the exercise program each young adult (now 9-11mo)or
aged (now 24-26 mo)rat wasanesthetized with alpha chloralose/ure-thane (500 and 100 mg/kg, respectively). The heartwas removed quickly and immersed inanoxygenated, pH balanced (pH 7.40) physi-ological salt solution that contained(in mM) 19.8 NaCl,4.5 KCI, 25.0NaHCO3, 1.2 KH2PO4, 1.2MgSO4,0.38CaCl2, and 10.0
dex-trose. AthinRVpapillarymuscle(<0.5 mm2 incross-sectionalarea) was then excised and placed inatemperature-controlled muscle chamber. The remainder of the heartwasseparated into the LVplus septum andRV, whichweregently blotted dry andcarefully weighed. Thesemeasurementshavebeen demonstratedtoagreecloselywith the calculatedwetweightsbasedon aconversion factor(wet/dry=4.545) derived from the driedweights (13).Atibiawasalso removed from the animalto serve as anindexofbodysize(10, 13).
TheexcisedRVpapillary musclewasmounted horizontallyin the muscle chamber betweentwoclips, oneof whichwasattachedto a
strain gauge (Statham UC2; Gould Inc., Houston, TX) for tension
measurement.The otherclip was attached to a micrometer for precise controlof changes in the muscle length. Nonrecirculated bathing fluid, maintained at280C, was passed continuously through the 0.5-ml chamberat 1 ml/min. The musclewasstimulatedto contract isomet-ricallyat12/min using square-wave pulses (0.2 ms in duration) that wereapplied through platinum plate electrodes at a stimulus strength thatexceeded threshold by - 25%. Afteran equilibration period of - 60 min the muscle wasstretched in small increments until it
reachedthelength at which the developed isometric tension was max-imal
(Lm,).Upon completion of each experiment this muscle length was measured,the muscle was carefully blotted dry and weighed, and its cross-sectional area was calculated (10, 13). The muscle was
as-sumed tohaveacross-sectionalareathatwasuniform along its length withadensity of 1.06 g/ml. The cross-sectional area was therefore
calculatedby dividingthe massby the density and the length.
Afteranadditional 30-min equilibration periodatLl,, in thefluid
whosecompositionwasdescribed above, theperfusate solution was
changedtoonethatwasalsowelloxygenated (Po2=500-600mmHg) but in which
[Ca2+]= 2.5 mM.This concentration of calciumwas
chosenbecause underpresentexperimentalconditions maximal devel-oped twitch force is achieved at
[Ca2+]e= 2.5 mM (10). After yet another30-min controlperiod, hypoxiawasinstitutedbyrapidly
containing 95% N2-5%CO2. The musclesremained in the hypoxic
environment for 20 min, after which time
hypoxia.The gas mixturewas bubbled into the warmed
tubing tightlyfitted intoaholeonthe side ofthe musclechamber canopy.
Althoughthe gas mixture of
anoxic,the muscle chamber canopy
completely airtight,sothat the
papillarymuscleinside the muscle bathwas
Aliquot samplesof the muscle chamber
througha side port in the muscle bath via
immediatelyonice and then
Alto, CA) (Dr.John
hypoxicgas mixture the
Po2in the muscle bath fluid was 544±18 mmHg.Lessthan5 min afteronsetof
hypoxiathePo2was 176±27 mmHg,and after 10 and 20 min of
hypoxiathemuscle bath solution hadPo2levels of 97±11 and 73±13
respectively. By10 min the oxygen tension had
since thetensionat20 minwas
value that wasslightly
higherthan that observedat 10 min. These
consistentlyat all three temperatures. They were also obtained
young and old animals. The oxygen tensionsweresimilarattheonset
of the three temperature
periods,sothatthemuscles started atthe
samelevel of oxygen tension for each temperature. The low levels of Po2 that have beenreported undercomparable (but not identical) conditions
investigatorswere 30 and 70
mmHg (14, 16).
Preliminarystudies demonstrated that cardiac
depressionoccurred when thePo2levels fell below - 300mmHg,alevelsimilartothat
developmentandits first derivativewere ob-tained from a universal
displayedand recorded on an
5', 10',15', and 20'of
reoxygenation period.The entire
equilibration)with the temperature of the
bathingfluid raised to 32 and thento
above,the oxygen tensionswere
procedureandthedeclinesof oxygen tensionwerealso thesame.
restingforce and themaximumforce
(RTI/2);maximum rate oftension
developmentnormalized for DT
The values are
expressedas means±SEM. Differences inmean
baselinevalues between thetwoage groupswereassessed
grouptheeffect of exercise and
analy-sis of variance
statistic,Dunnett's test was
At theend of the chronic exercise program the youngadult
exercisedgroupremainedvirtually unchanged in weight, while their
progressivelygained weight (Table I). Incontrast,the old exercisedrats notonly didnotgain but actually lost weight slightly, while their age-matched controls gained weight. The basal systolic blood pressure was similar amongthe fourgroups(young exercised= 134±4,young con-trol = 130±5, old exercised = 139±6, old control = 133±6
mmHg). The basal heartratewasalso
comparableamongthe groups(young exercised = 409±14, youngcontrol =
old exercised = 384±11, old control =
young adult exercised group demonstrated a significant
de-crease inresting heartratecompared with their age-matched controls (young exercised=-64±25,youngcontrol=
P <0.05). The old exercised groupshowed a significant de-cline in resting systolicpressure(old exercised = -20±6, old
-4+7,P < 0.05). Both age groups demonstrated improved exercise tolerance, requiring less prodding and showing less fatigue,attheend of thetraining period. These changes show that bothagegroupsadaptedtoexercise condi-tioning.Inthesedentary animals significantLV hypertrophy, but no significant RV hypertrophy, was present in theaged compared with theyoungadult controlrats. Chronic exercise did notalter the heart weight/tibia length ratio in eitherage group(Table I).
Theeffects of chronic exerciseontheisometric contractile response to hypoxia are presented in Table II. Hypoxia re-sultedinsignificant declinesinthe contractileperformance of both theyoungadult andsenescentgroups. Atbaseline there were no significant differences between aged
exercisedand aged controlratsorbetweenyoungadult exercised andyoung adult controlratsinthecontractileparameters, DTand(dT/
dtmax)/DT.However, during hypoxia significant differences between the exercised andage-matched controlsbecame
ap-parentforboththeyoungadultandsenescentanimals(Table II). Chronic exercise clearly increased myocardial tolerance and preserved contractile performance during hypoxia. The DT and
(-dT/dtm.)/DTin response to hypoxia wereboth significantly preserved in the exercised animals, ascompared with the controls for bothagegroups.The time required fora
20%depression of developed tension (from baseline value)was
significantly lengthened(by>60%)as aresultofchronic ex-erciseinbothage groups (Fig. 1). The timecourseofthe
de-Table II. Effect
Papillar Musclesin YoungAdult and Old ExercisedRatsand Their
Performance (percent of basal value
Variable Basal values 5 min 10 min 15min 20 min
Control(8) 13.2±2.4 90±1 80±3 71±3 64±3 Exercised (9) 16.6±1.8 97±1*
89±2*82±3§ 76±4§ (dT/dtm,,)/DT(s-')
Control(8) 18.8±0.9 93±1 83±3 76±4 70±4 Exercised (9) 18.1±0.3 96±1§ 90±2§ 84±3 79±4 (-dT/dtmax)/DT
Control(8) 13.3±0.8 90±2 79±3 71±4 64±4
Exercised (9) -12.1±0.4
97±2*89±3§ 82±3§ 76±4§ Old adult
Control(8) 21.4±4.7 89±2 82±2 72±2 62±3 Exercised (7) 20.0±6.1 96±2 89±2§ 83±2§ 78±2t
Control(8) 17.2±0.8 90±2 84±3 75±2 65±4 Exercised (7) 16.8±0.6 97±1 92±2§ 87±2§
Control(8) 9.6±0.8 91±2 81±2 72±2 62±3 Exercised (7) 12.4±0.7 96±2 91±2t 84±2§ 78±2t
cline and restoration ofDTin responseto
ofbasal value the declines of
and old controlDTwere
tension development (dT/dt)was
than in controls
-dT/dt in bothage groups
The indices of relaxation
appearedto be more
con-traction, demonstrating largerpercent
Young adultrats(9.5 mo) Senescent rats (25 mo)
Variable Control (8) Exercised (9) Control (8) Exercised (7)
Body weight, initial(g) 272±6 262±3 380±20 358±18
Body weight, terminal(g) 350±7*
ABodyweight(g) 78±9 3±11t 23±13 -37±28
LVweight/body weight(X10-3) 1.85±0.04
2.30±0.11"12.05±0.10 2.51±0.15§ RVweight/body weight(X10-3) 0.45±0.02 0.54±0.04 0.41±0.04 0.48±0.04
LVweight/tibia length(g/cm) 0.158±0.006 0.150±0.005 0.184±0.009 0.179±0.011
RVweight/tibia length(g/cm) 0.037±0.003 0.036±0.004 0.037±0.005 0.035±0.002 Papillarymusclecross-sectionalarea(mm2) 0.40±0.04 0.38±0.05 0.40±0.07 0.42±0.04
*P<0.00 1, compared with initial value. tP<0.001; FP<0.05;11P<0.005, compared with age-matchedcontrols.
re-W * * quired fora20% reduction in cardiac 10 performance
(DT)of isometric twitch
at lo10 _ t * 1 t inRVpapillarymusclesofyoung
adultcontrol(YC), young adult exer-o cised(YE),old adult control(OC),
and old adultexercised
320C*P<0.05vs.age-matched con-YC YE OC OE trol animals.
interaction ofchronic exercise and
investigated(Table III). At
contractileand the relaxation processes were quickened as
temperaturewas increased for all groups.
andthe percent change in basal values of
intheold control (309%)
thanin the young
protective effect of exercisetraining on cardiac function during
hypoxiawaspresent at 32 and
280C exercise conferredno noticeable protective
(dT/dtm.)/DTin young adults and
RTI/2for both agegroups. DT,
38than at 28 or
320C forboth groups of young adult rats (Table
hypoxia-induced reductionin these parame-terswas
smaller inyoung adult
exercisedthan in young adult control rats.
oppositeeffects on the
RTI/2at 28 and
380C(Table III and
prolonged with hypoxia in all fourgroups. At
320Cthe young adult
exercised and controlgroups also demonstrated
during hypoxia.However, the
old exercised and old control
became prolonged inthe
old exercisedand shortened in the old controls.
Apparently the transitionaltem-perature
hyp-100 '| OE
90 - ~~~~~~~oc
-0 0 5
70 HYPOXIA REOXYGENATION
-5 0 5 10 15 20 5 10 15 20
Figure 2.Effect ofhypoxiaandreoxygenationonDTin isometri-cally contractingRVpapillarymusclesfromagedexercisedand
re-spective age-matched sedentary controlrats at320C,
mM.*P<0.05; **P<0.01; ***P<0.001vs.age-matched controls. Abbreviationsaresame asinFig. 1.
z 0 0
Figure3.Theeffect of hypoxiaondT/dt(top) and-dT/dt(bottom)of isometrically
mus-cles fromyoungadult and old adult exercised andrespective
age-matched control ani-mals. Abbreviationsare
oxiaoccurs at a
slightlylower temperature in the younger
animal exercise training is associated
lowering of this transitionaltemperature to a
major findings. First, chronic
exhibited by bothyoung
protective effect of exercisewasmost
relaxation phase of the isometric twitchmore than the
con-tractile phase in bothagegroups.
Second, the transitionaltem-perature at
which hypoxia neither shortenednor
agedrat than in the young
lowered the transitionaltemperature
this study demonstrateda clear
change. This isbecause
thoughboth groupsweremaintainedon anadlib
they demonstratedadecrease in
to the blood
trainedon the same
regimenthat had been shown
EffectofTemperatureandExerciseTraining on Cardiac Response to Hypoxia in Young Adult and Old ExercisedRatsand Their Age-matched Controlsat
280C 320C 380C
Variable Basalvalue Hypoxia (20) Basal value Hypoxia (20') Basal value Hypoxia(20)
%basal % basal % basal
Control (8) 13.1±0.76 85±2 19±1 70±3 25±2 55±4
Exercised (9) 12.8±0.27 86±3 18±0.3 79±4 27±1 66±5
Control(8) 7.6±0.53 74±3 13±1 64±4 20±2 47±3
Exercised (9) 6.9±0.39 80±3 12±0.4 76±4* 22±0.3 59±5
Control(8) 85.6±3.36 96±1 50±2 102±3 27±2 105±5
Exercised (9) 95.1±5.01 95±2 54±2 101±2* 25±0.2 104±4*
Control (7) 12.4±0.8 83±3 17±1 65±4 24±1 60±4
Exercised (7) 13.1±0.3 88±4 18±1 83±2§ 29±1 73±3§
Control(7) 5.5±0.52 80±4 10±1 62±3 17±1 58±4
Exercised (7) 7.1±0.77 84±2 12±1 78±2§ 23±1 72±3§
Control(7) 131.9±7.82" 95±3
100.2±11.73'94±4 54±3 107±2*§ 26±0.4§ 114±4*
All values are means±SEM. * P<0.05;§ P<0.005,comparedwithage-matchedcontrols.
"lP <0.005, comparedwith young adult controls.
restingblood pressure. We believe that these
age-related cardiovascular adaptionto
exercisesity and duratioi
training, i.e., bradycardiain young
hypotension inOurfinding 1
(10). Other observers have alsonotedthe absence did not result
change during exercise training(10, with other obsei
investigatorshave noted a lowering of blood consistently acc pressure alone (24). Thus,
it islikely that the magnitude of Our results
function ofthe species, the mode of contraction and
exercise conditii senceofsignifica
6 A tionof
oxia is not estab
YECYE0 muscle of traine4
-2 trols.A seconda
-6T 1 S
-8 show a training
28 32 38 drial oxygen
Temperature('C) trolindex, phosl
Figure 4. Effect of hypoxia (20 min) on cardiac relaxation (changes ity (32). Nevertl intimetoRT,,2)inisometrically contractingRVpapillary muscles metabolic dowr from young adult and aged exercisedratsandtheirrespective age- taining glycolyt matchedcontrols at28, 32, and
380C.*P <0.05, compared with versed Pasteur value at
280C.Abbreviations are same asinFig. 1. membranes or]
tP<0.05, compared with valueat
that moderate treadmill exercise
is inagreement rvers
substantial functional changes in.
relaxation of cardiac musclemay accompany
intensityeven in the ab-ant
hypertrophy (6, 11,
underlying the exercise-induced
hyp-lished, but several possibilitiesmay be
consid-rcise-induced increases in cardiac actomyosin
their sedentary age-matched
efficiency of utilization of
exercise traininghas not been shown to I
ATP, creatine phosphate,or
(32). Studieshave also
i-regulatory capacity by
main-;ic fluxat the
same level during
(33). Theselatter mechanisms have been demonstrated tobe present in hypoxia-tolerant cells and absent in hypoxia-sensi-tive cells (34).
Furthermore, it has been demonstratedthatcardiac mito-chondrial oxidative phosphorylation in response to stress de-clines withageand that in theratthis declinebecomes appar-entbetween 10 and 15 mo ofage(35). Studies performed on aged rats using both isolated and perfused heart preparations have shown improved cardiac oxidative performance with training (5, 6, 11, 12). This improved performance of the sen-escent trained myocardium isaccompanied by increased LV cytochrome cconcentrations and ratesof oxidation of gluta-mate-malate, palmitoylcarnitine, and succinate (5), none of which occurs in the exercise-trained young adult hearts (5, 32). Therefore,training-induced enhancement of myocardial phys-ical performance is associated with increased oxidativeenergy metabolism in the aged heart.
Theeffect oftraining on hypoxia-induced changes in myo-cardial relaxation probably involves the sarcoplasmic reticu-lum. It has been demonstrated that an increase in the rate of
Ca>2accumulation occurs in the sarcoplasmic reticulum of young adult hearts after chronic exercise (7-8 wk of swim-ming), and this is associated with faster relaxation times (36). Ourstudy supports other reports that hypoxia has a relatively greater inhibitory effect on relaxation than on contraction (14, 16).
Furthermore, we found that the relaxation phase also ap-pearedtobemoretemperaturesensitive than the contraction phase. Our observations are similar to those reported for rat skeletal muscle (37) and for rat LV papillary muscle (38), whose
calcium sequestrationis correspondingly temperature sensitive
traininginthe old rat
improvedcardiac muscle performance during both hypoxia and
hypothermiais compatible with the notion that these
training-inducedimprovements may share the same
In summary, the present study demonstrates that even in the absence of cardiac
hypertrophyexercise training reverses and
performanceof senescent and young adult rats
hypothermia.The relaxation phase appears to
bemoresensitive than the contraction phase to
WethankDr.J.Eichorn for technical assistance, Dr. D. Rigney for helpful suggestions, andJ.Longstreet,S.Dahlgren,and J.Raglandfor assistance inmanuscriptpreparation.
This studywassupported inpartby HL-29295, National Heart, Lung and Blood Institute,andtheVeteransAdministration.
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