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gH2AX Foci Analysis

Histon H2AX is phosporylated rapidly in response to

DNA double-strand breaks (DSB), leading to the forma-

tion of nuclear foci visualized by immunocytochemical

detection of gH2AX. gH2AX analysis is an exquisitely

sensitive technique to monitor DSB repair, amenable for

use with very low doses.

2-(Carbamimidoyl-Methyl-Amino)Acetic Acid

Creatine

Ca2+

Release ChannelsExcitationContraction Coupling

Ryanodine Receptors

Ca2+-Induced Ca2+ Release (CICR)

Ca2+-induced Ca2+ release (CICR) in myocytes is medi-

ated via opening of ryanodine receptors on the SR.

Ryanodine receptors are activated by adjacent L-typevoltage-operated Ca2+ channels, which are in turn acti-

vated by depolarized plasma membranes. CICR subse-

quently leads to significant elevation of Ca2+ levels

intracellularly, allowing Ca2+ to bind to myofilament pro-

teins and initiate contraction of myocytes.

Caffeine

JAYNEM. KALMAR

Wilfrid Laurier University, Waterloo, ON, Canada

Synonyms3,7-dihydro-1,3,7-trimethyl-1 H-purine-2,6-dione;1,3,7-

trimethylxanthine;1,3,7-trimethyl-2,6-dioxopurine

DefinitionCaffeine (1,3,7-trimethylxanthine) is a plant alkaloid

with a purine structure. Its chemical formula is

C8H10N4O2 and it has a molecular weight of 194.19 g.

Pharmacologically, caffeine is most frequently defined as

a central nervous system stimulant, although it is also

a weak diuretic and smooth muscle relaxant [1].

DescriptionCaffeine is an alkaloid that can be extracted from plants

such as tea leaves, cacaoseeds, cola nuts, and coffee beans or

synthesized from uric acid. Once purified, caffeine is

a white crystalline substance that is somewhat soluble in

water (as caffeine citrate) and many organic solvents.

Caffeine has a number of dimethylated metabolites includ-

ing paraxanthine, theobromine, and theophylline

that differ with respect to the number and location of

methyl groups on their purine heterocyclic ring structure

(Fig. 1). Paraxanthine is the primary metabolite of caffeine

that acts as a central nervous system stimulant with potency

similar to caffeine. The metabolites theobromine and the-

ophylline are also naturally occurring plant alkaloids. Asindicated by its chemical name (1,3,7-trimethylxanthine),

caffeine has three methyl groups positioned on N1, N3, and

N7 of the purine ring structure [1].

Pharmacologically, caffeine is best known for its

actions as a central nervous system stimulant; however,

Frank C. Mooren (ed.),Encyclopedia of Exercise Medicine in Health and Disease, DOI 10.1007/978-3-540-29807-6,# Springer-Verlag Berlin Heidelberg 2012
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the drug is sufficiently small and hydrophobic to cross the

blood-brain barrier and other cell membranes and there-fore has the capacity to affect many tissues depending on

its concentration. Caffeine and other methylxanthines are

used therapeutically to prevent drowsiness, to treat mild to

moderate headaches in combination with analgesics, and

to treat apnea and arrhythmias in preterm infants [1].

Caffeine is approved by the US Food and Drug Adminis-

tration as a safe and effective stimulant and is available

over the counter. Three mechanisms of caffeines actions

have been observed in vitro: (1) intracellular calcium

mobilization via direct interaction with calcium channels

in the sarcoplasmic reticulum, (2) phosphodiesterase

inhibition, and (3) adenosine receptor antagonism [2].

The first two of these three mechanisms require millimolar

concentrations of caffeine that would be toxic in humans.

Nonetheless, it has been suggested that endogenous

modulators such as ATP may potentiate caffeine and

paraxanthines effects on the ryanodine receptor to

increase intracellular calcium concentration in intact skel-

etal muscle preparations. If this is the case, caffeine may

alter muscle function in vivo at concentrations much

lower than predicted by in vitro studies. In contrast, caf-

feine functions as an adenosine receptor antagonist at

caffeine concentrations in the micromolar range associ-

ated with plasma and brain levels following low to mod-erate oral doses of the drug. Accordingly, the widespread

effects of caffeine on human tissues are largely attributed

to antagonism of adenosine receptors [2].

ApplicationCaffeine is well known for its effects on wakefulness and

mental alertness. In 1958, Axelsson and Thesleff reported

that caffeine could generate muscle contractions in the

absence of neural or electrical activation, suggesting that

this legal, widely available, and socially acceptable drug

may improve both physical and mental performance. Sev-

eral decades of research have since clearly established that

caffeine is indeed ergogenic, enhancing performance in

many types of sports and exercise. It is now clear, however,

that the primary mechanism for these ergogenic effects

is via adenosine receptor antagonism rather than direct

effects on muscle.

Caffeines effects on human performance are most

evident in endurance sports such as running and cycling.

In these sports, dosages ranging from 3 to 9 mg/kg body

weight have been found to increase time to exhaustion or

time trial performance in placebo-controlled studies [4].

Caffeine. Fig. 1 Caffeine is a trimethylated xanthine that is metabolized to three dimethylated xanthines including

theobromine, theophylline, and paraxanthine. Caffeine, theobromine, and theophylline are plant alkaloids widely consumed in

a variety of foods and beverages such as coffee, tea, and chocolate, while the primary metabolite, paraxanthine, is only found

endogenously. Due to its structural similarity to adenosine, caffeine acts as a competitive adenosine receptor antagonist. This is

the primary mechanism for caffeines effects as a central nervous system stimulant

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The effects of caffeine on high-intensity exercise are not as

clear. There are some reports that caffeine improves per-

formance on tests of anaerobic power, such as the Wingate

test, and other studies that report no effect of caffeine or

a decline in anaerobic performance in the caffeine trail

compared to placebo. In tests of anaerobic performance, it

appears that caffeine is more likely to enhance the perfor-

mance of trained athletes than untrained individuals [3].

Although caffeine is a weak diuretic, it does not appear

to alter sweat rate and total body water loss to an extent

that would impair performance or pose any risk to the

athlete [3].

Because caffeine is distributed to all body compart-

ments, it is difficult to isolate the biological mechanisms

responsible for its ergogenic effects. Previously, caffeine

was thought to enhance endurance performance through

enhanced lipolysis and glycogen sparing secondary to

phosphodiesterase inhibition and increased catecholaminerelease. However, caffeine does not inhibit phosphodiester-

ase activity at physiological doses and while caffeine is

associated with elevated plasma epinephrine levels, there

is very little evidence to suggest that caffeine enhances fat

oxidation [4]. Consequently, it is now generally accepted

that the ergogenic effects of caffeine are not of a metabolic

origin and focus has shifted to alternative theories.

One possibility is that caffeine enhances skeletal mus-

cle contractile force, although there is some question as to

whether physiological levels of caffeine would be sufficient

to elicit the increase in intracellular calcium observedin vitro. Most human studies report no effect of caffeine

on twitch amplitude, twitch half relaxation time, or max-

imal instantaneous rate of twitch relaxation in either

unfatigued or fatigued human muscle [5]. However, caf-

feine does offset the decline in tetanic force observed

during low-frequency electrical stimulation of muscle.

Because low-frequency fatigue has been attributed to

a reduction in calcium release by the ryanodine receptor, it

is possible that caffeine improves contractile output of

fatigued muscle under some conditions.

Placebo-controlled studies report increased muscle

activation and endurance times following caffeine admin-

istration that could not be attributed to changes in neu-

romuscular transmission or muscle contractile function.

This suggests that caffeine may also enhance human per-

formance via central mechanisms [5]. Adenosineis an

endogenous neuromodulator that exerts a tonic inhibi-

tory influence in the central nervous system by decreasing

excitatory neurotransmitter release and the firing rates of

central neurons. Due to its structural similarity to adeno-

sine, caffeine functions as an adenosine receptor antago-

nist and reverses many of the inhibitory effects of

adenosine at microMolar concentrations [2]. Caffeine has

been found to increase neurotransmitter release and firing

rates via A1 receptor antagonism, increase dopaminergic

transmission, and increase spontaneous motor activity

and treadmill running time of rats [5]. In human studies

of corticomotor excitability, caffeine potentiates cortically

evoked potentials and reduces the duration of the cor-

tical silent period. It also increases the amplitude of the

Hoffman reflexand self-sustained firing of motor units

which suggests that the drug may also act on the neuro-

muscular system at a spinal level. Finally, caffeine is asso-

ciated with reductions in pain and force sensation which

may contribute to enhanced endurance performance [5].

Restricting or banning a substance consumed in foods

and beverages by many people on a daily basis poses

a challenge to anti-doping agencies. In the past, the Inter-

national Olympic Committee (IOC) restricted the use of

caffeine by athletes, allowing a maximal urine level of12 mg/ml. Over 95% of ingested caffeine, however, is

excreted as paraxanthine-derived urinary metabolites

rather than caffeine. As such, athletes would have to con-

sume approximately 9 mg of caffeine per kg body weight

to reach the IOC urinary caffeine limit whereas ergogenic

effects have been demonstrated following oral caffeine

dosages as low as 3 mg/kg body weight. Although caffeine

use is not prohibited by the World Anti-Doping Agency

(WADA), it is monitored for use in competition via the

WADA Monitoring Program for the purposes of detecting

patterns of misuse of this stimulant in sport. Use ofcaffeine out of competition is not monitored.

References1. Brunton LB, Lazo JS, Parker KL (eds) (2005) Goodman & Gilmans

the pharmacological basis of therapeutics, 11th edn. McGraw-Hill,

New York

2. Fredholm BB (1995) Astra award lecture. Adenosine, adenosine

receptors and the actions of caffeine. Pharmacol Toxicol 76:93101

3. Goldstein ER, Ziegenfuss T, Kalman D, Kreider R, Campbell B,

Wilborn C, Taylor L, Willoughby D, Stout J, Graves BS,

Wildman R, Ivy JL, Spano M, Smith AE, Antonio J (2010) Interna-

tional society of sports nutrition position stand: caffeine and perfor-

mance. J Int Soc Sports Nutr 7:54. Graham TE (2001) Caffeine and exercise: metabolism, endurance

and performance. Sports Med 31:785807

5. Kalmar JM (2005) The influence of caffeine on voluntary muscle

activation. Med Sci Sports Exerc 37:21132119

Calcium

Calcium is a chemical element belonging to the group of

alkaline earth metals. It has the atomic number 20 and an

Calcium C 147

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atomic mass of 40.078 Da. Ca is named as a macroelement

as the Ca content of humans amounts to about 1 kg, which

is used predominantly for mineralization of bones. Impor-

tant food sources include milk and milk products, nuts,

and vegetables such as broccoli, beans, and collard greens.

Serum Ca is under hormonal control, e.g., calcitriol, cal-

citonin, and parathyroid hormone, and its typical concen-

tration range is between 2.1 and 2.6 mmol/L. There exists

a steep concentration gradient for calcium across the

plasma membrane as the intracellular levels are around

100200 nmmol/L. This gradient is an important prereq-

uisite for calciums role as an important intracellular sig-

naling factor thereby activating many cellular processes

such as myofilament contraction, gating of ion channels,

derangement of cytoskeletal and organelle structures, and

gene expression.

Cross-References Intracellular Signaling

Calmodulin

Calmodulin (CaM) is an abbreviation for calcium-

modulated protein, which is an important calcium-binding

protein ubiquitously expressed in eukaryotic cells. It

contains four so-called EF-hands motifs, which represent

the calcium-binding unit. Upon Ca2+ binding, calmodulinbecomes an important regulator of several intracellular tar-

gets which are involved in processes such as inflammation,

immune response, metabolism, apoptosis, cell growth, etc.

Canaliculi

Small canals that run through the bone matrix. Fluid flows

through these canals when strain is applied to bone. This

fluid flow is thought to stimulate bone formation.

Cancer

Cancer is a group of diseases characterized by uncontrolled

growth and spread of abnormal cells. If the spread is not

controlled, it can result in death. Cancer is caused by both

external (e.g., tobacco, chemicals, radiation, infectious

organisms, etc.) and internal (e.g., inherited mutations,

hormones, immune conditions, metabolic conditions,

etc.) factors. These casual factors may act together or in

sequence to initiate or promote carcinogenesis.

Cancer Cachexia

A complex metabolic syndrome associated with underly-

ing illness and characterized by skeletal muscle wasting

with or without loss of fat mass. It is associated with

muscle weakness and fatigue and accounts for more

than 20% of all cancer-related deaths. Cancer cachexia is

associated with reduced mobility, increased risk of com-

plications in surgery, impaired response to chemo-/

radiotherapy, and increased psychological distress, leading

to an overall reduction in qualityof life. Cachectic pertains

to a state of poor health, malnutrition, and weight loss.

Cancer Survivorship

Term given to describe individuals who have been diag-

nosed with cancer from the point of diagnosis through

end of life.

Cancer, Prevention

BRIGIDM. LYNCH, CHRISTINEM. FRIEDENREICH

Department of Population Health Research, Alberta

Health Services Cancer Care, Calgary,

AB, Canada

SynonymsMalignancy;Neoplasm;Tumor

DefinitionCancerdescribes diseases that arise when normal regen-

erative processes are disrupted by uncontrolled cell growth

or by cellular loss of the ability to undergo apoptosis.

Abnormal cells continue dividing, forming tumors that

can spread to other tissues via invasion or metastasis.

Cancer can originate nearly anywhere in the body. The

most common type of cancer, carcinoma, begins in the

skin or in cells that line or cover internal organs, such as

the lungs or colon. Other forms of cancer include sarcoma

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(arises in bone, cartilage, fat, muscle, or other connective

tissue); myeloma (plasma cells); lymphoma (lymphatic

system); and leukemia (white blood cells).

Each year, an estimated 13 million people are diag-

nosed with cancer, and there are approximately eight

million cancer-related deaths [1]. Breast cancer is the

leading cancer site amongst women (representing 23% of

new diagnoses and 14% of deaths), whilst lung cancer is

the most frequently diagnosed cancer in men (17% of new

diagnoses and 23% of deaths) [1]. Cancer is the leading

cause of death in developed countries, and the second

most common cause of death in developing countries

[1]. The developing world has cancer incidence rates

approximately half those seen in the developed world;

however, overall cancer mortality rates are similar. The

poorer cancer survival rates in developing countries is

likely due to the disease being diagnosed at a later stage

and limited access to appropriate treatments [1].The burden of disease is expected to increase globally:

by 2030, the number of people with cancer is projected to

double, to more than 20 million new cases [2]. This

increase will be partly attributable to population growth

and aging, but also because of increasing adoption of

a western lifestyle amongst the developing world.

Hence, a disproportionate increase in cancer incidence

will occur within the developing world in years to come.

Pathogenesis

The etiological pathway leading to cancer is a complexone, involving a series of changes that likely occur over

decades. Various models of carcinogenesis have been

proposed, but generally there are four definable stages:

initiation, promotion, progression, and malignant conver-

sion. Initiation describes the point at which genetic errors

occur spontaneously when cells divide or as a result of

exposure to carcinogens. Cells have a number of mecha-

nisms to repair damaged DNA, but if repair does not

occur, the mutated cells may begin to replicate (promo-

tion), eventually becoming a benign tumor. During

progression, the tumor cells continue to replicate and

additional mutations may occur in genes that regulate

growth and cell function. These changes contribute to

further growth until malignant conversion occurs.

Epidemiological studies have identified a wide range of

environmental and genetic factors associated with

increased cancer risk. Some environmental risk factors,

such as tobacco smoking, alcohol consumption, exposure

to UVradiation, dietary intake, and physical activity levels,

are modifiable. Hence, a large proportion of common

cancers are potentially preventable. Expert review has con-

cluded that approximately one third of cancer cases are

attributable to tobacco smoking or exposure, and another

third of cases are due to a combination of poor diet,

physical inactivity, and overweight/obesity [2].

Physical activity is thought to reduce cancer risk via

a number of biological mechanisms [3]. These mecha-

nisms may impact different stages of carcinogenesis: for

an in-depth review, see [4]. Key biological mechanisms by

which physical activity may reduce cancer risk include:

AdiposityPhysical activity may reduce body fat, which is associated

with colon, postmenopausal breast, endometrial, ovarian,

kidney and esophageal cancers, and cancer-related mor-

tality. Adiposityis likely an independent contributor to

cancer risk, and it may facilitate carcinogenesis through

a number of pathways, including increased levels of sex

hormones, insulin resistance, chronic inflammation,

and altered secretion of adipokines.

Endogenous Sex HormonesPhysical activity decreases endogenous sex hormone levels

and increases circulating sex hormone binding globulin

(SHBG). Exposure to estrogens/androgens is a risk factor

for breast, endometrial, ovarian, and prostate cancers.

SHBG may affect cancer risk by binding to sex hormones,

rendering them biologically inactive.

In premenopausal women, estrogens are predomi-

nantly produced by the ovaries. Very high levels of physical

activity might lower estrogen exposure by delaying onset ofmenarche, causing menstrual irregularity or reducing the

total number of menstrual cycles. For postmenopausal

women, adipose tissue is the primary source of endogenous

estrogens. Physical activity may decrease adiposity and thus

production of estrogens. In men, the effect of physical

activity on androgen levels is unclear, but dihydroxy-

testerone (a testosterone metabolite) may be increased.

Insulin ResistancePhysical activity improves insulin sensitivity by increasing

the number and activity of glucose transporters in both

muscle and adipose tissue. In addition, physical activity

may indirectly reduce insulin resistance by promoting

fat loss and preservation of lean body mass. Associations

between insulin levels and colorectal, postmenopausal

breast, pancreatic, and endometrial cancers have been

demonstrated in epidemiological studies. Fasting

glucose levels have been directly associated with pancre-

atic, kidney, liver, endometrial, biliary, and urinary

tract cancers.

Neoplastic cells use glucose for proliferation; there-

fore, hyperglycemia may promote carcinogenesis by

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providing an amiable environment for tumor growth.

High insulin levels increase bioavailable insulin-like

growth factor-I, which is involved in cell differentiation,

proliferation, and apoptosis. Decreasing blood insulin

levels also results in increased hepatic synthesis of

SHBG; hence, insulin indirectly increases bioavailability

of endogenous sex hormones.

InflammationPhysical activity may decrease levels of proinflammatory

factors, namely adipokines (leptin, tumor necrosis

factor-a, interleukin-6) and C-reactive protein, and

increase anti-inflammatory factors (adiponectin).

Chronic inflammation is acknowledged as a risk factor

for most types of cancer.

Obesity represents a low-grade, systematic inflamma-

tory state. It has been hypothesized that perpetual cell

proliferation, microenvironmental changes, and oxidativestress associated with chronic inflammation could dereg-

ulate normal cell growth to promote malignancy.

Other Possible MechanismsPhysical activity results in improved pulmonary function,

which may promote expulsion of carcinogenic agents

from the lungs. This mechanism is specific to physical

activity and lung cancer.

Physical activity may increase circulating levels of

25-hydroxyvitamin D, possibly through increased ultravi-

olet radiation exposure as a result of time spent outdoors.In addition, vitamin D is fat soluble and is readily

stored in adipose tissue. Hence, physical activity may

also increase vitamin D levels by reducing adiposity.

Vitamin D has been associated with colorectal, breast,

and pancreatic cancer risk.

Regular, moderate physical activity may also modulate

the immune systems ability to recognize and repair or

eliminate damaged cells.

It is likely that these proposed mechanisms are inter-

related, and that the relative contribution of each mecha-

nism varies by cancer type. Further research is required to

elicit a clearer understanding of the biological mecha-

nisms involved in the pathways between physical activity

and cancer [3].

Training/Exercise ResponseThe association between physical activity and cancer has

been systematically reviewed by international agencies [2]

and individual scientists [3,5]. The level of epidemiolog-

ical evidence varies by cancer site. There is convincing

evidence that physical activity decreases the risk of devel-

oping colon cancer, probable evidence for an effect on

breast and endometrial cancer, and possible evidence for

a reduced risk of developing ovarian, prostate, and lung

cancer [3,5].

Epidemiological reviews estimate that physical activity

reduces colon cancer risk by 2025% amongst both men

and women who report participation in the highest level

of physical activity assessed, compared with men and

women who report participating in the lowest level of

physical activity. There is a 25% average breast risk

reduction amongst most physically active women com-

pared to least active women. A stronger physical activity-

associated risk reduction exists amongst postmenopausal

women. For endometrial cancer, reviews have concluded

that physical activity reduces risk by 2030%. There is

consistent evidence for a doseresponse effect for colon

and breast cancer, whereas for endometrial cancer a dose

response effect has been found in approximately half of

all studies.Whilst the evidence is weaker for ovarian, prostate

and lung cancers, epidemiological reviews estimate that

risk reductions are modest (1020%) for ovarian and

prostate cancer. For lung cancer, there appears to be no

effect of physical activity on risk amongst nonsmokers.

However, there may be substantial risk reductions (20

40%) among smokers. The associations between physical

activity and cancer risk for other sites are either null or

there is insufficient evidence to draw any conclusions

about the link.

It remains unclear what type and dose of physicalactivity are required to achieve significant cancer risk

reductions. Randomized, controlled trials are required to

provide answers about these areas of uncertainty. None-

theless, there is strong and consistent epidemiological

evidence that physical activity reduces the risk of several

major cancers types. Public health guidelines for physical

activity and cancer prevention recommend 3060 min

of moderate-to-vigorous-intensity physical activity per

day [2].

References1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011)

Global cancer statistics. CA Cancer J Clin 61:6990

2. World Cancer Research Fund, The American Institute for Cancer

Research (2007) Food, nutrition, physical activity, and the preven-

tion of cancer: a global perspective. American Institute for Cancer

Research, Washington, DC

3. Friedenreich CM, Neilson HK, Lynch BM (2010) State of the

epidemiological evidence on physical activity and cancer prevention.

Eur J Cancer 46:25932604

4. Rundle A (2005) Molecular epidemiology of physical activity and

cancer. Cancer Epidemiol Biomarkers Prev 14:227236

5. Courneya KS, Friedenreich CM (eds) (2011) Recent results in cancer

research: physical activity and cancer. Springer, Heidelberg

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Cancer, Therapy

LEEW. JONES

Department of Surgery, Duke University Medical Center,

Duke Cancer Institute, Durham, NC, USA

SynonymsExercise and cancer-related side effects; Exercise and

prognosis after cancer diagnosis

DefinitionThe benefits of physical activity to reduce the primary and

secondary risk of cardiovascular-related diseases have

been recognized since antiquity. The first formal investi-

gation was not until the early 1950s when James Morris

and colleagues reported that occupational exercise wasassociated with substantial reductions in coronary heart

disease in the seminal London Busmen study [1]. This

pioneering work led to extensive epidemiological investi-

gation of the association between both occupational

and leisure-time exercises and the risk of cardiovascular

disease by numerous research groups. As a result of the

burgeoning evidence, in 1995, the American College of

Sports Medicine and Centers for Disease Control

published the first prescription guidelines to encourage

increased participation in exercise in Americans of all ages

for health promotion and disease prevention [2]. Over thepast 15 years, physical activity guidelines have been

published for secondary prevention of numerous chronic

conditions, including type II diabetes, chronic obstructive

pulmonary disease, heart failure, and heart transplant

recipients [3].

The putative relationship between exercise and

cancerwas not formally recognized until 2002 wherein

the American Cancer Society recommended regular

exercise to reduce the risk of breast, colon, and several

other forms of cancer. In contrast, investigation of the role

of exercise following a diagnosis of cancer has, until

recently, received scant attention. The precise reasons forthis are not known but likely reflect the prevailing dogma

that a cancer diagnosis and associated therapeutic man-

agement preclude participation in and benefit from phys-

ical activity. The reversal of interest in exercise results from

the alignment of several factors including recognition of

cancer survivorshipas a major public health concern,

a stronger evidence base, and strong interest of cancer

patients themselves in pursuing adjunct approaches to

optimize recovery and longevity. In the past decade, how-

ever, exerciseoncology research has become increasingly

recognized as a legitimate and important field of research

in cancer management [4]. This review will provide an

overview of the putative evidence supporting the role of

exercise across the cancer survivorship continuum (i.e.,

diagnosis to palliation).

CharacteristicsThe use of conventional and novel cytotoxic therapies

is associated with a diverse range of debilitating physio-

logical (e.g., deconditioning, skeletal muscle atrophy, cardiac

and pulmonary dysfunction) and psychosocial (e.g., fatigue,

nausea, depression, anxiety) toxicities that impair recovery

and increase susceptibility to concomitant age-related con-

ditions [5]. To address these concerns, in the mid- to late

1980s, researchers initiated the first studies to explore

whether structured physical activity may be an appropriate

intervention to mitigate chemotherapy- and radiation-

induced fatigue and anticipated loss of functional capacityamong women with early-stage breast cancer. Since this

early work, 80 studies have now examined the safety,

feasibility, and preliminary efficacy of structured physical

activity interventions on a broad range of physiological

and psychosocial outcomes before, during, and/or follow-

ing cancer therapy. Since this early seminal work, the

number of publications has steadily increased over the

past 20 years, with studies becoming progressively more

sophisticated in scope, design, and size to address the

major questions in the field. A chronological timeline of

significant landmarks in exerciseoncology research ispresented inFig. 1.

Several excellent systematic reviews and meta-analyses

have evaluated the pertinent literature [6]. Findings of

these reviews indicate that structured exercise training is

a safe and well-tolerated intervention associated with

favorable improvements in cancer-related symptoms and

functional outcomes both during and following the com-

pletion of adjuvant therapy. To summarize, the majority of

studies were conducted in women with early breast cancer,

with fewer studies in nonsmall-cell lung cancer (NSCLC),

hematologic malignancies, or mixed cancer populations.

Exercise modality consisted of aerobic training alone,

resistance training alone, or the combination of aerobic

and resistance training prescribed at a moderatevigorous

intensity (5075% of baseline maximum heart rate or

cardiorespiratory fitness), three sessions or more per

week, for 1060 min per exercise session. The length of

the exercise training ranged from 2 to 24 weeks. Overall,

exercise was associated with significant improvements in

muscular strength, cardiorespiratory fitness, functional

quality of life (QOL), fatigue, anxiety, and self-esteem.

Few adverse events (AEs) were observed. It was concluded

Cancer, Therapy C 151

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that exercise is a beneficial adjunct therapy both during

and following the completion of adjuvant therapy in adult

cancer patients, with low incidence of AEs [6].

To further clarify this issue, Jones et al. [7] conducted

a meta-analysis to determine the effects of supervised

exercise training on cardiorespiratory fitness, including

only those studies employing a randomized controlleddesign and direct measurement of peak oxygen consump-

tion (VO2peak), the gold standard assessment of cardiore-

spiratory fitness. Cardiorespiratory fitness is determined

by the integrative capacity of the cardiopulmonary system

(i.e., pulmonarycardiacvascularskeletal muscle axis) to

deliver oxygen from the atmosphere to muscle mitochon-

dria. Cardiorespiratory fitness is one of the most powerful

predictors of cardiovascular and all-cause mortality in

healthy adults as well as those with cardiovascular disease

(CVD) even after controlling for traditional CVD risk

factors.

Jones et al. [7] only identified a total of six studies thatmet eligibility criteria involving a total of 571 adult cancer

patients (n= 344, exercise; n= 227, usual-care control).

Pooled data indicated that exercise training was associated

with a statistically significant increase in VO2peak(WMD = 2.91 mLkg1min1; 95% CI, 1.184.64) withminimal adverse events, although significant heterogene-

ity was evident in this estimate (I2 = 87%). It was con-

cluded that the effect of exercise on VO2peakis promising

but the current evidence base is emergent with many

fundamental questions (e.g., optimal prescription, timing,

and setting of exercise; effects of exercise on tumor biol-

ogy; and therapeutic efficacy) remaining to be addressed.

In the following sections, we review the efficacy of

exercise training in specific areas across the cancer survi-

vorship continuum (i.e., presurgery, postsurgery during

adjuvant therapy, survivorship (following the completion

of primary adjuvant therapy), and palliation), with a viewtoward areas requiring future research.

Clinical Relevance

Exercise Therapy Prior to Surgical ResectionSurgery is the most common form of cancer therapy

for patients with solid tumors. Pulmonary resection is

the treatment of choice for a variety of disorders, includ-

ing non-small cell lung cancer and selected cases of

oligometastatic disease (sarcoma, colorectal cancer, mela-

noma, etc.), and involves removal of a substantial portion

of lung parenchyma that can negatively impact VO2peak. Inaddition, the majority of lung cancer patients also present

with several significant concomitant comorbid diseases.

The extent of surgery, together with comorbid disease,

significantly complicates the treatment process, and peri-

operative and postoperative complications are common.

In order to evaluate complication risk, cancer surgeons

often assess VO2peakto determine preoperative physiologic

status of operable candidates. VO2peakis strongly inversely

associated with surgical complication rate in NSCLC

patients. Given this, an important question is whether

1986 2001 2002 2003 2005

Jones et al. [11] investigates the interaction between exercise and chemotherapy efficacy in a

mouse model of breast cancer

Holmes et al. [13] reports that self-reported regular exercise is

associated with substantial

reductions in breast-cancer specific and all-cause mortality

2007 2008 2009

First study toinvestigate thefeasibility andeffects of exercise

training in

patients withcancer [30]

Kolden et al. [28]investigates theeffects of thecombination of

aerobic andresistance training

First randomized trial is launched

by the National Cancer Institute of

Canada to investigate the effects

of exercise on disease-free

survival in patients with operable

colon cancer following the

completion of adjuvant therapy [30]

Segal et al. [27] reports theeffects of aerobic training in

women undergoingchemotherapy for operablein the Journal of Clinical

Oncology

The American Cancer Society

convenes a group of expertsto create exerciserecommendations for cancerpatients in CA: A Cancer

Journal for Clinicians [29]

First studies to comparethe effects of differenttypes of exercise in

patients with cancer [10]

The benefit of exercise onmortality in colon cancermay be influenced bytumor molecular

expression of p27 [14]

Cancer, Therapy. Fig. 1 Exerciseoncology research timeline

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exercise training prior to surgical resection can improve

VO2peakand, in turn, lower surgical complications.

To date, two studies have addressed the initial feasibil-

ity, tolerability, and potential efficacy of presurgical

exercise-based rehabilitation in patients diagnosed with

NSCLC. In the first study, Jones et al. [8] examined the

efficacy of presurgical aerobic training on VO2peakamong

20 patients with suspected NSCLC. Mean VO2peakincreased by 2.4 mLkg1min1 from baseline to

presurgery. Exploratory analyses indicated that

presurgical VO2peak decreased postsurgery but did not

decrease beyond baseline values. In the second study,

Bobbio et al. [9] reported that short-term exercise-

based pulmonary rehabilitation increased VO2peak by

2.8 mL kg1min1 prior to pulmonary resection in

12 NSCLC patients with chronic obstructive disease.

Larger randomized trials investigating the efficacy of exer-

cise training on surgical complications and postsurgicalrecovery in cancer patients appear warranted.

Exercise Therapy During Adjuvant TherapyThe use of anticancer therapies is associated with unique

and varying degrees of direct and indirect physiological

injury that dramatically reduces patients ability to toler-

ate exercise (i.e., low VO2peak), predisposing them to

morbidity, poor psychosocial functioning, and increase

susceptibility to concomitant age-related conditions [5].

To address these concerns, in mid- to late 1980s,

researchers explored whether structured exercise trainingmay be an effective intervention to prevent and/or

mitigate adjuvant therapyassociated toxicities and poor

cardiorespiratory fitness among women with early-stage

breast cancer. Since these early studies, approximately

40 studies have been conducted, investigating the safety,

tolerability, and efficacy of structured exercise training

on symptom control and other pertinent outcomes in

patients undergoing cancer therapy. In summary, the

current evidence base provides promising evidence that

exercise training is a well-tolerated and safe adjunct ther-

apy that can mitigate several common treatment-related

side effects among patients undergoing different types of

cytotoxic therapy, including chemotherapy, radiation,

and androgen deprivation therapy (ADT).

In addition to examining symptom control, a question

of significant importance is whether the effects of exercise

are similar among those patients undergoing therapy as

those who have completed therapy. The meta-analysis by

Jones et al. [7] indicated that exercise training was associ-

ated with superior VO2peak improvements following

adjuvant therapy compared to during adjuvant therapy,

although no study has formally investigated this question.

For example, Courneya et al. [10] found that17 weeks of

aerobic training did not improve VO2peakamong women

receiving anthracycline-containing chemotherapy for

early breast cancer. Similarly, Jones et al. reported that

14 weeks of aerobic training led to negligible improve-

ments in VO2peak

among patients undergoing cisplatin-

based adjuvant chemotherapy for early NSCLC. It is also

important to stress that although exercise training caused

minimal improvements in VO2peak, these effects occurred

against the background of declines in VO2peakin patients

assigned to the control condition; in the study by

Courneya et al., VO2peakdeclined 5% among womenrandomized to usual-care control. Intriguingly, several

other studies have reported significant improvements in

VO2peakand other pertinent outcomes in patients receiv-

ing other types of conventional cytotoxic therapies, such

as radiation and ADT. These findings suggest that

exercise-induced adaptations in the cardiopulmonarysystem may be contingent on the type of cytotoxic therapy

being administered.

Another question that has received less attention but is

one of critical importance is whether exercise impacts the

therapeutic efficacy of conventional or novel cytotoxic

agents. Exercise is a potent multifactorial intervention

that influences a wide spectrum of pathways that could

potentially modulate the cytotoxicity of chemotherapeu-

tic agents. Jones et al. [11] investigated the effects of

8 weeks of forced exercise (treadmill running) on the

antitumor efficacy of

doxorubicinin female mice bear-ing human breast cancer xenografts. Overall, there were

no significant differences on tumor growth between

groups receiving doxorubicin alone versus doxorubicin

plus exercise training (p= 0.33), suggesting that exercise

does not significantly modulate doxorubicin-induced

breast cancer growth inhibition. However, further work

by Jones et al. [12] found that although tumor growth was

comparable between exercised and sedentary animals

bearing orthotopically implanted breast cancer xeno-

grafts, tumors from exercising animals had significantly

improved blood perfusion/vascularization relative to the

sedentary control group, suggesting that aerobic exercise

can significantly increase intratumoral vascularization,

which may normalize the tumor microenvironment

and, in turn, inhibit tumor cell metastatic dissemina-

tionand improve therapeutic efficacy. Future studies are

required to test these intriguing questions.

Exercise Therapy Following the Completionof Adjuvant Therapy (Survivorship)Improvements in early detection and surveillance together

with more effective locoregional and systemic therapies

Cancer, Therapy C 153

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have led to significant survival gains for individuals

diagnosed with early-stage cancer. Indeed, 13 million

Americans who have been diagnosed with cancer are

alive today. However, it is becoming increasingly apparent

that improved outcomes in patients with early stage

disease may come at the price of therapy-induced late

effects. As a result, there has been a significant paradigm

shift toward long-term therapy-associated toxicity and its

resultant effects on morbidity, premature noncancer,

competing causes of mortality, and QOL.

Exercise has emerged as an intervention of central

importance in cancer survivorship, with numerous

research groups examining whether exercise performed

following the completion of therapy can accelerate recov-

ery from the rigors of adjuvant cytotoxic therapy [4].

Similar to during therapy, the current literature base

suggests that exercise is a safe and well-tolerated therapy

associated with significant improvements in certain phys-iological and psychosocial therapy late effects.

A major goal in exerciseoncology survivorship

research is to determine the optimal exercise prescription

in cancer survivors. The vast majority of studies to date

have investigated the effects of either aerobic training

alone, resistance training alone, or the combination of

aerobic and resistance training following traditional exer-

cise prescription guidelines (35 day week1 at 5075% of

baseline VO2peakfor 1215 weeks) in cancer survivors. As

the field progresses, it will be important to conduct ade-

quately powered studies that identify the optimal type,intensity, duration, and frequency of exercise training to

improve symptom control in cancer survivors. At least

three ongoing trials are addressing different aspects of

this question in NSCLC, breast, and prostate cancer sur-

vivors. Of particular interest is high-intensity exercise

training. Several recent randomized trials have demon-

strated that high-intensity aerobic training (i.e., 75%

of baseline exercise capacity) causes superior improve-

ments in VO2peakrelative to low- or moderate-intensity

exercise training in patients with or at risk of CVD. How-

ever, there is a dearth of data regarding effects of exercise

intensity following a cancer diagnosis.

Arguably, one of the most important questions in

exerciseoncology research is to determine whether the

benefits of exercise extend beyond to impact prognosis

following a cancer diagnosis [4,6]. The extant literature

indicates that, in general, regular physical activity is asso-

ciated with 1561% reduction in the risk of death from

breast or colorectal cancer (Table 1). The association

between physical activity and cancer-specific mortality is

not uniform and appears to vary according to volume

of physical activity and even cancer type. In breast cancer,

the amount of physical activity that was significantly

inversely associated with cancer death ranged from

9 MET-h week1 (brisk walking for 30 min, 5 dayweek1) to 21 MET-h week1 (brisk walking for

75 min, 5 day week1); in colorectal cancer, the range

was

18 MET-h week1 (brisk walking for 60 min, 5 day

week1) to 27 MET-h week1 (brisk walking for 90 min,5 day week1). In addition, exploratory analyses suggest

that the effects of physical activity may also differ by

histological subtype and tumor expression of certain

molecular markers. For example, Holmes et al. [13]

reported that 9 MET-h week1 was associated witha relative risk reduction in mortality of only 9% in

women with estrogen receptor (ER)negative tumors rel-

ative to a mortality reduction of 50% in women with ER-

positive tumors. Meyerhardt et al. [14] reported that the

association between exercise and mortality in patients

with stage IIII colon cancer may depend on p27 status.Specifically, in tumors with loss of p27, the HR for colon

cancer mortality was 1.40 (95% CI, 0.414.72) for patients

reporting 18 MET-h week1 relative to those reporting


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Cancer, Therapy. Table 1 Association between postdiagnosis physical activity and cancer-specific mortality and all-cause

mortality following a cancer diagnosis

Cancer site/

author N Cohort/setting

Cancer-specific mortality All-cause mortality

Risk

reduction

(HR) Exercise dose

Dose

response

Risk

reduction

(HR)

Exercise

dose

Dose

response

Breast cancer

Holmes

et al. [13]

2,987 Stages IIII; Nurses

health study

0.50a 914.9

METs-h

weekb

No 0.56a 1523.9

METsbNo

Sternfeld

et al. [16]

1,970 Stages IIIIa; Life after

cancer epidemiology

0.69a 3


12/86

receiving aggressive combination cytotoxic and support-

ive care therapies. As such, these patients are likely

experiencing more disease-related and treatment-related

toxicities that will modify the exercise response.

A recent systematic review by Lowe et al. [15] identi-

fied a total of six studies investigating the effect of exercise

training on symptom control in patients with advanced

cancer. In general, all studies reported positive findings,

but overall, methodological quality was poor. There is

currently insufficient evidence for definitive conclusions

regarding the tolerability, safety, or efficacy of exercise in

cancer patients with advanced disease. Given the poorer

prognosis and elevated treatment toxicity in this setting,

we stress the importance of rigorous AE and safety mon-

itoring in planned exercise studies is comparable to that

required for pharmaceutical intervention trials, in con-

junction with appropriate correlative science components.

Such an approach will ensure the optimal safety andefficacy of exercise in this unique setting.

SummaryResearch, as well as clinical interest, in the role of exercise

following a cancer diagnosis has increased dramatically

and is likely to increase even further over the next decade

with the emergence and increasing importance placed on

cancer survivorship. The current evidence base provides

strong but preliminary evidence that exercise training is

a well-tolerated and safe adjunct therapy that can mitigate

several common treatment-related side effects amongpatients receiving adjuvant therapy for early-stage disease.

Results of these first-generation studies provide a solid

platform to launch second-generation studies that will

extend the scope and application of exerciseoncology

research to address the major unanswered questions in

this emerging field.

AcknowledgementsDr. Jones is supported by NIH CA143254, CA142566,

CA138634, CA133895, CA125458 and George and Susan

Beischer.

References1. Morris JN, Heady JA, Raffle PA et al (1953) Coronary heart disease

and physical activity of work. Lancet 265:111120

2. Pate RR, Pratt M, Blair SN et al (1995) Physical activity and public

health. A recommendation from the Centers for Disease Control and

Prevention and the American College of Sports Medicine. J Am Med

Assoc 273:402407

3. Warburton DE, Nicol CW, Bredin SS (2006) Health benefits of

physical activity: the evidence. Canadian Med Assoc J 174:801809

4. Jones LW, Peppercorn J (2010) Exercise research: early promise

warrants further investment. Lancet Oncol 11:408410

5. Jones LW, Eves ND, Haykowsky M et al (2009) Exercise intolerance in

cancer and the role of exercise therapy to reverse dysfunction. Lancet

Oncol 10:598605

6. Schmitz KH, Courneya KS, Matthews C et al (2010) American

College of Sports Medicine roundtable on exercise guidelines for

cancer survivors. Med Sci Sports Exerc 42:14091426

7. Jones LW, Liang Y, Pituskin EN et al (2011) Effect of exercise training

on peak oxygen consumption in patients with cancer: a meta-

analysis. Oncologist 16:112120

8. Jones LW, Eves ND, Peddle CJ et al (2009) Effects of presurgical

exercise training on systemic inflammatory markers among patients

with malignant lung lesions. Appl Physiol Nutr Metab 34:197202

9. Bobbio A, Chetta A, Ampollini L et al (2008) Preoperative pulmo-

nary rehabilitation in patients undergoing lung resection for non-

small cell lung cancer. Eur J Cardiothorac Surg 33:9598

10. Courneya KS, Segal RJ, Mackey JR et al (2007) Effects of aerobic

and resistance exercise in breast cancer patients receiving adjuvant

chemotherapy: a multicenter randomized controlled trial. J Clin

Oncol 25:43964404

11. Jones LW, Eves ND, Courneya KS et al (2005) Effects of exercise

training on antitumor efficacy of doxorubicin in MDA-MB-231breast cancer xenografts. Clin Cancer Res 11:66956698

12. Jones LW, Viglianti BL, Tashjian JA et al (2010) Effect of aerobic

exercise on tumor physiology in an animal model of human breast

cancer. J Appl Physiol 108:343348

13. Holmes MD, Chen WY, Feskanich D et al (2005) Physical activity and

survival after breast cancer diagnosis. J Am Med Assoc 293:24792486

14. Meyerhardt JA, Ogino S, Kirkner GJ et al (2009) Interaction of

molecular markers and physical activity on mortality in patients

with colon cancer. Clin Cancer Res 15:59315936

15. Lowe SS, Watanabe SM, Courneya KS (2009) Physical activity as a

supportive careintervention in palliative cancer patients:a systematic

review. J Support Oncol 7:2734

16. SternfeldB, Weltzien E, Quesenberry CP Jr et al (2009) Physical activity

andrisk of recurrence andmortality in breastcancer survivors: findingsfrom the LACE study. Cancer Epidemiol Biomarkers Prev 18:8795

17. Holick CN, Newcomb PA, Trentham-Dietz A et al (2008) Physical

activity and survival after diagnosis of invasive breast cancer. Cancer

Epidemiol Biomarkers Prev 17:379386

18. Irwin ML, Smith AW, McTiernan A et al (2008) Influence of pre- and

postdiagnosis physical activity on mortality in breast cancer survi-

vors: the health, eating, activity, and lifestyle study. J Clin Oncol

26:39583964

19. Pierce JP, Stefanick ML, Flatt SW et al (2007) Greater survival after

breast cancer in physically active women with high vegetable-fruit

intake regardless of obesity. J Clin Oncol 25:23452351

20. Dal Maso L, Zucchetto A, Talamini R (2008) Effect of obesity

and other lifestyle factors on mortality in women with breast cancer.

Int J Cancer 123:21889421. Meyerhardt JA, Heseltine D, Niedzwiecki D et al (2006) Impact of

physical activity on cancer recurrence and survival in patients with

stage III colon cancer: findings from CALGB 89803. J Clin Oncol

24:35353541

22. Meyerhardt JA, Giovannucci EL, Holmes MD et al (2006) Physical

activity and survival after colorectal cancer diagnosis. J Clin Oncol

24:35273534

23. Meyerhardt JA, Giovannucci EL, Ogino S et al (2009) Physical activity

and male colorectal cancer survival. Arch Intern Med 169:21022108

24. Kenfield SA, Stampfer MJ, Giovannucci E et al (2011) Physical activ-

ity and survival after prostate cancer diagnosis in the health

professionals follow-up study. J Clin Oncol 29:726732

156C Cancer, Therapy


13/86

25. Moorman PG, Jones LW, Akushevich L et al (2011) Recreational

physical activity and ovarian cancer risk and survival. Ann Epidemiol

21:178187

26. Ruden E, Reardon DA, Coan AD et al (2011) Exercise behavior,

functional capacity, and survival in adults with malignant recurrent

glioma. J Clin Oncol 29(2):29182923

27. Segal R, Evans W, Johnson D et al (2001) Structured exercise

improves physical functioning in women with stages I and II breast

cancer: results of a randomized controlled trial. J Clin Oncol

19:657665

28. Kolden GG, Strauman TJ, Ward A et al (2002) A pilot study of group

exercise training (GET) for women with primary breast cancer:

feasibility and health benefits. Psycho Oncol 11:447456

29. Brown JK, Byers T, Doyle C et al (2003) Nutrition and physical

activity during and after cancer treatment: an American Cancer

Society guide for informed choices. CA Cancer J Clin 53:268291

30. Courneya KS, Booth CM, Gill S et al (2008) The colon health and

life-long exercise change trial: a randomized trial of the national

cancer institute of Canada clinical trials group. Curr Oncol

15:279285

Capillarization

Angiogenesis

Capillary Hematocrit

The ratio of red blood cells (RBCs) to plasma volume

within the capillaries at any given time. The number ofRBCs within the capillaries that lie adjacent to the

myocytes determines, in part, the O2 diffusion capacity

(DO2).

Carbohydrate

Nutrition

Carbohydrate Loading

A. N. BOSCH

Human Biology, University of Cape Town MRC Research

Unit for Exercise Science and Sports Medicine, Sports

Science Institute of South Africa, Newlands, South Africa

SynonymsGlycogen loading;Glycogen super-compensation

DefinitionCarbohydrate loading is the use of a dietary technique used

primarily by endurance athletes before participation in

prolonged events such as the marathon. It involves ingestion

of high-carbohydrate foods or drinks for 13 days before

competition to increase muscle glycogen stores.

Mechanism of ActionIn 1967, the introduction of the needle biopsy technique

for the sampling of muscle tissue in exercise physiology

studies provided important new data on the relationships

between diet, muscle glycogen concentration, and fatigue

during prolonged exercise.

Muscle Glycogen ConcentrationsUsing the biopsy technique, initial studies determined that

the concentration of glycogen in the leg muscles ofuntrained people eating a normal diet varies from approx-

imately 80 to 120 mmol/kg of wet muscle (ww), whereas

average muscle glycogen concentrations of athletes who

ingest a diet high in carbohydrate and are in training are

somewhat higher, around 130 mmol/kg ww [1]. Values as

high as 140200 mmol/kg ww are attained in trained

athletes who have not exercised for 2448 h and who

have consumed a high-carbohydrate diet.

Muscle Glycogen Concentrations, Diet, and

Exercise PerformanceDiet can affect both muscle glycogen content and exerciseperformance. Possibly the best known studies that con-

tributed to the development of the dietary practice that

was to become known as carbohydrate loading are those

of Ahlborg et al. [2] and Bergstrom et al. [3] in which

muscle glycogen concentrations were manipulated

through various combinations of diet and exercise. In

these studies, muscle glycogen concentration was found

to average 97 mmol/kg ww at the start of exercise. Subjects

then cycled to exhaustion at 75% of VO2maxon a cycle

ergometer, which averaged 114 min. Following this initial

exercise bout, for the next 3 days a high fat-protein dietwas ingested, after which muscle glycogen concentrations

had decreased to 35 mmol/kg ww and average exercise

time to exhaustion was reduced to 57 min. The dietary

regimen was then changed to a high carbohydrate one for

the next 7 days. With this regimen, mean muscle glycogen

concentrations increased to 184 mmol/kg ww and exercise

time increased to 167 min. Thus, it became apparent that

initial glycogen concentration influenced exercise time to

exhaustion, and that muscle glycogen concentration could

be influenced by dietary manipulation. It was not long

Carbohydrate Loading C 157

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before this procedure of first depleting muscle glycogen

stores by an exercise bout followed by 3 days of a diet low

in carbohydrate (high fat-protein diet), followed subse-

quently by eating a large amount of carbohydrate (600 g

of carbohydrate daily), was used by endurance athletes in

an effort to enhance performance. This became known as

the carbohydrate loading diet, although the period of

high carbohydrate intake became reduced from 7 to 3 days

when used by athletes.

Importantly, this original work was done using rela-

tively untrained people in the experiments. Subsequently,

it was demonstrated that the depletion phase of eating

only protein and fat is unnecessary in well-trained athletes

[4,5]. Simply eating a high-carbohydrate diet for 3 days

(500600 g/day; 10 g/kg body weight/day), combined

with a reduction in training, was found to result in similar

amounts of glycogen being stored to that obtained

when the original loading regimen was followed. This isbecause glycogen synthase, one of the enzymes involved

in muscle glycogen synthesis, is activated by the carbohy-

drate and glycogen depletion regimen in untrained

people; in trained individuals, however, glycogen synthase

is already maximally activated as a result of daily training

and no further activation occurs following a period of low

carbohydrate intake.

More recently, it has been shown that in highly trained

athletes even 3 days of carbohydrate loading is longer than

needed to maximize muscle glycogen stores. By ingesting

10 g/kg body weight/day of carbohydrate, maximal muscleglycogen concentrations can be attained within 24 h [6,7].

Carbohydrate loading with high glycemic index car-

bohydrate foods rather than low glycemic index foods

has been found to have no effect on performance in

a 10-km performance run, after an initial run for 1 h at

70% VO2max[8]. Unfortunately, muscle glycogen concen-

tration was not measured in this study, and the total

exercise performed may not have been sufficient to deplete

muscle glycogen stores, and therefore, it cannot be

assumed that the high glycemic index foods did not result

in higher initial muscle glycogen stores, based only there

being no differences in performance in this particular

study. The effect of glycemic index on the rate of muscle

glycogen storage remains to be resolved. It should be

noted, however, that in the study which showed that

maximal muscle glycogen stores could be attained within

24 h, a high glycemic index carbohydrate was ingested to

carbohydrate load.

Once a high muscle glycogen concentration has been

attained by carbohydrate loading, it is possible for an

athlete to maintain these high concentrations without

continued loading. Specifically, the muscle glycogen

concentration remains elevated for 3 [9] to 5 days [10],

provided only moderate intensity exercise of approxi-

mately only 20 min duration is performed during

that time.

Following the findings of Bergstrom et al. [3] of

increased dietary carbohydrate resulting in increased mus-

cle glycogen stores and an apparently related increase in

exercise time to exhaustion, a number of papers were

published which examined in greater detail the relation-

ship between diet, muscle glycogen content, and the pos-

sibility of improved exercise performance. These studies

showed that fatigue in endurance exercise appeared to

consistently coincide with low muscle glycogen concen-

trations, and it was therefore concluded that exhaustion

during prolonged exercise was due to muscle glycogen

depletion. Therefore, starting exercise with raised muscle

glycogen levels by prior carbohydrate loading was con-

firmed as being advantageous. In some respects, however,the coincidence between muscle glycogen depletion and

exhaustion during prolonged exercise may be an over

simplification, as in many of the studies that examined

the effect of carbohydrate loading on performance, blood

glucose concentration was either not measured or not

carefully considered when results were analyzed. It appears

that in some studies which attributed fatigue to depleted

muscle glycogen stores, lowered blood glucose concentra-

tion could also have accounted for the fatigue experienced

by the subjects. Nevertheless, the majority of studies have

shown that starting exercise with high muscle glycogenconcentration delays the onset of fatigue.

Although, in some cases, low blood glucose concen-

trations together with low muscle glycogen concentration

make interpretation of the cause of fatigue difficult, the

importance of muscle glycogen concentrations alone was

demonstrated in a study in which subjects started exercise

with either high or low muscle glycogen content as a result

of ingesting a diet either low in carbohydrate or after

having carbohydrate loaded for 4 days prior to the exper-

iment. As expected, time to fatigue was longer in the

athletes with high initial muscle glycogen content. At

exhaustion, glucose was infused to restore plasma glucose

to pre-exercise levels. Interestingly, although this elimi-

nated symptoms of hypoglycemia, it did not improve

performance time, suggesting that muscle glycogen

depletion specifically, and not hypoglycemia was respon-

sible for exhaustion in these subjects. In contrast,

Coyle et al. [11] showed that exercise could be continued

even when muscle glycogen content was low, provided

that the blood glucose concentration remained high.

Cyclists ingested either a glucose polymer solution or

water placebo while cycling at 70% of VO2max. Those

158C Carbohydrate Loading


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subjects ingesting the carbohydrate solution were able to

exercise for an hour longer than subjects ingesting the

placebo, even though the muscle glycogen concentrations

of the carbohydrate ingesting subjects during the final

hour were as low as those of the subjects who could not

continue and who were exhausted. Thus, it was concluded

that it could not have been muscle glycogen depletion that

stopped the subjects from continuing to exercise, but

rather an inadequate supply of plasma glucose for oxida-

tion. The final conclusion of the study was that as long as

the muscle was provided with sufficient glucose to oxidize,

exercise could be continued when normally this would not

be possible because hypoglycemia terminated exercise pre-

maturely. However, if the data are examined carefully, it

becomes apparent that the muscle glycogen concentra-

tions at exhaustion in this study did not reach the very

low concentrations that are usually associated with

exhaustion. Values were around 40 mmol/kg ww, whereasit has previously been reported that 1728 mmol/kg ww is

the concentration consistent with exhaustion [12]. Thus,

it is likely that the ergogenic effect of the carbohydrate was

mainly due to the maintenance of euglycemia, and there-

fore the concept of muscle glycogen being implicated in

exhaustion remains.

One of the few field studies that have investigated the

theory that glycogen depletion is an important element in

the cause of fatigue is that of Karlsson and Saltin [12].

Using well-trained subjects, they found that after follow-

ing a carbohydrate-loading regimen, subjects ran a fastertime in a 30-km road race than when eating a normal diet.

Of particular interest was the finding that loading did not

result in a faster initial running speed. Rather, it allowed

the athletes to maintain their initial speed for longer

before slowing down. The time in the race at which the

runners slowed down correlated with their starting muscle

glycogen concentrations.

Although there have been many studies that have

concentrated on the effect of high muscle glycogen con-

centration subsequent to carbohydrate loading on

endurance exercise performance at moderate intensity

(70% VO2max), there have also been studies which have

shown that even if exercise intensity is low, high muscle

glycogen content at the start of exercise is important. For

example, muscle glycogen depletion has been implicated

in exhaustion in exercise performed as low as 43% of

VO2max. At the other extreme, it has also been shown

that exercise at very high exercise intensities (greater

than 80% VO2max) may also be affected by muscle glyco-

gen content at the start of exercise. Specifically, an increase

in time to exhaustion after carbohydrate loading and

decreased time to exhaustion after glycogen depletion

compared to exercise which commenced with normal

muscle glycogen levels, has been shown when exercise

was performed at 100% of VO2max. This was despite the

short duration of exercise performed at such a high

intensity.

Despite the majority of studies showing a positive

effect on exercise performance as a result of starting exer-

cise with high muscle glycogen content after carbohydrate

loading, there have been some that have shown no effect.

For example, in one study, there was no difference in

running time to fatigue (77 min) at 7580% of VO2maxbetween carbohydrate-loaded and non-loaded groups

of well-trained runners. Glycogen concentrations at

exhaustion, however, were too high in both groups to

be considered a possible cause of fatigue (125 and

100 mmol/kg ww, respectively). Similarly, a field trial

over a distance of 21 km showed no improvement in

running performance as a result of prior carbohydrateloading. The failure to show an improvement over this

distance is most likely due to muscle glycogen stores not

becoming depleted before the end of the 21-km distance.

Other studies, however, have shown an effect over

a distance of 25 km. Thus, although there is some

conflicting evidence, generally it appears that carbohy-

drate loading only becomes important when exercise

duration is so long, or of such high intensity that muscle

glycogen becomes depleted during the event. It is also

important to remember that fatigue can occur due to

factors other than muscle glycogen depletion or lowblood glucose concentration. For example, Costill et al.

[13] found that trained runners may became fatigued

even though muscle glycogen concentrations at exhaus-

tion were 63 mmol/kg ww in the vastus lateralis and

86 mmol/kg ww in the soleus.

In summary, carbohydrate loading increases muscle

glycogen concentration, which has generally been shown

to enhance endurance performance, and in some studies,

to enhance shorter duration exercise performed at

a higher intensity.

References1. Sahlin K, Katz A, Broberg S (1990) Tricarboxylic acid cycle interme-

diates in human muscle during prolonged exercise. Am J Physiol

259(5 Pt 1):C834C841

2. Ahlborg B, Bergstrom J, Brohult J et al (1967) Human muscle glyco-

gen content and capacity for prolonged exercise after different diets.

Forvarsmedicin 3:8599

3. Bergstrom J, Hermansen L, Hultman E, Saltin B (1967) Diet, muscle

glycogen and physical performance. Acta Physiol Scand 71(2):

140150

4. Sherman WM, Costill DL, Fink WJ, Miller JM (1981) Effect of

exercise-diet manipulation on muscle glycogen and its subsequent

utilization during performance. Int J Sports Med 2(2):114118

Carbohydrate Loading C 159

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16/86

5. Costill DL, Sherman WM, Fink WJ et al (1981) The role of dietary

carbohydrates in muscle glycogen resynthesis after strenuous run-

ning. Am J Clin Nutr 34(9):18311836

6. Bussau VA, Fairchild TJ, Rao A et al (2002) Carbohydrate loading in

human muscle: an improved 1 day protocol. Eur J Appl Physiol

87(3):290295

7. Fairchild TJ, Fletcher S, Steele P et al (2002) Rapid carbohydrate

loading aftera shortbout of near maximal-intensity exercise.Med Sci

Sports Exerc 34(6):980986

8. Chen Y, Wong SH, Xu X et al (2008) Effect of CHO loading patterns

on running performance. Int J Sports Med 29(7):598606

9. Goforth HW Jr, Arnall DA, Bennett BL, Law PG (1997) Persistence of

supercompensated muscle glycogen in trained subjects after carbo-

hydrate loading. J Appl Physiol 82(1):342347

10. Arnall DA, Nelson AG, Quigley J et al (2007) Supercompensated

glycogen loads persist 5 days in resting trained cyclists. Eur J Appl

Physiol 99(3):251256

11. Coyle EF, Coggan AR, Hemmert MK, Ivy JL (1986) Muscle glycogen

utilization during prolonged strenuous exercise when fed carbohy-

drate. J Appl Physiol 61(1):165172

12. Karlsson J, Saltin B (1971) Diet, muscle glycogen, and enduranceperformance. J Appl Physiol 31(2):203206

13. Costill DL, Sparks K, Gregor R, Turner C (1971) Muscle glycogen

utilization during exhaustive running. J Appl Physiol 31(3):353356

Carbon Dioxide Output

Gas Exchange, Alveolar

Cardiac Arrhythmias

ALESSANDRO BLANDINO, ELISABETTA TOSO, FIORENZO GAITA

Cardiology Division, Department of Internal Medicine,

San Giovanni Battista Hospital, University of Turin,

Turin, Italy

SynonymsAbnormal cardiac electrical activity; Disturbance of the

heartbeat;Rhythm disorder

DefinitionThe term arrhythmia comes from the ancient Greek

a-rhuthmos) and identifies a loss of normal heart activity.

Cardiac arrhythmias can be classified into bradyarrhythmias

(when heart rate is < than 60 beats for minute) or

Tachyarrhythmias (when heart rate is >than 100 beat

for minute), that may arise from supraventricular

regions or ventricles. Bradyarrhythmias include sinus bra-

dycardia, wandering pacemaker, sinus pause, and

atrioventricular blocks. Supraventricular tachyarrhyth-

mias include premature ectopic beats, AV nodal reentrant

tachycardia (AVNRT), orthodromic AV reentrant tachy-

cardia (AVRT) due to an Accessory Pathway, ectopic

atrial tachycardia, atrial fibrillation (AF), and atrial flutter

(AF1). Ventricular tachyarrhythmias include premature

ectopic beats, non-sustained ventricular tachycardia,

idio-ventricular accelerated rhythm, benign idiopathic

ventricular tachycardia, and malignant ventricular

tachycardia, such as sustained ventricular tachycardia,

polymorphic ventricular tachycardia, torsades de pointes,

and ventricular fibrillation.

Characteristics and Eligibility for SportsPractice

Bradyarrhythmias

In the trained athlete, sinus bradycardia (defined assinus heart rate < 60 beats per minute) and sinus pauses

are frequent and are generally benign conditions, second-

ary to high vagal tone and reduced sympathetic tone

(Bradyarrhythmias). These conditions are generally

asymptomatic and do not affect maximum heart rate attain-

ment. Anyway, if symptomatic, 24-h Holter monitoring and

exercise testing are recommended, plus echocardiography

whether structural heart disease is suspected.

High vagal tone and reduced adrenergic tone are also

responsible for the high prevalence of atrioventricular

(AV) blocks in athletes. In AV block, atrial activation isconducted to the ventricles with a delay, or it is not

conducted at all, during a period when the AV conduction

pathway (AV node or His-Purkinje system) is not expected

to be refractory. On the basis of the electrocardiographic

criteria, AV block is classified as first, second, or third

degree, and depending on the anatomical point at which

the conduction of the activation wave front is impaired, it

is described as supra-Hisian, intra-Hisian, or infra-Hisian.

In the athletes, the most common AV blocks seen are

as follows: first-degree AV block (each atrial stimulus

is conducted to the ventricles with a prolonged PR

interval more than 200 ms) and second-degree AV block

type I (Wenckebach or Mobitz I, defined as progressively

increased PR interval until an atrial stimulus is not

conducted to the ventricles). AV blocks typically occur

during sleep or at rest and resolve during exercise, showing

the supra-hisian nature of conduction impairment.

If asymptomatic, with no cardiac disease, and with

resolution of block during exercise, the athlete is eligible

for all sports. In case of severe bradycardia (heart rate

3 s, and when symptomatic, it

is necessary to interrupt any sports activity and further

160C Carbon Dioxide Output
http://dx.doi.org/10.1007/978-3-540-29807-6_83http://dx.doi.org/10.1007/978-3-540-29807-6_83http://dx.doi.org/10.1007/978-3-540-29807-6_4011http://dx.doi.org/10.1007/978-3-540-29807-6_4158http://dx.doi.org/10.1007/978-3-540-29807-6_4158http://dx.doi.org/10.1007/978-3-540-29807-6_4508http://dx.doi.org/10.1007/978-3-540-29807-6_3108http://dx.doi.org/10.1007/978-3-540-29807-6_3108http://dx.doi.org/10.1007/978-3-540-29807-6_2004http://dx.doi.org/10.1007/978-3-540-29807-6_2004http://dx.doi.org/10.1007/978-3-540-29807-6_2173http://dx.doi.org/10.1007/978-3-540-29807-6_2173http://dx.doi.org/10.1007/978-3-540-29807-6_2173http://dx.doi.org/10.1007/978-3-540-29807-6_2004http://dx.doi.org/10.1007/978-3-540-29807-6_3108http://dx.doi.org/10.1007/978-3-540-29807-6_4508http://dx.doi.org/10.1007/978-3-540-29807-6_4158http://dx.doi.org/10.1007/978-3-540-29807-6_4158http://dx.doi.org/10.1007/978-3-540-29807-6_4011http://dx.doi.org/10.1007/978-3-540-29807-6_83


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diagnostic monitoring (24-h Holter monitoring and

exercise testing) be recommended. At least after 3 months

when the symptoms are absent, physical effort can be

restarted with yearly clinical controls.

TachyarrhythmiasAs previously described, tachyarrhythmias are classifiedinto supraventricular (when they originate from atria or

AV junction) and ventricular (when they originate from

myocardium under the AV junction).

Supraventicular Arrhythmias

Premature Supraventricular ComplexSupraventricular premature ectopic beats (PSVCs) are

premature activation of the atria or AV junction arising

from a site other than the sinus node. They are a common

finding in many individuals, including athletes, and theymay be asymptomatic or cause mild symptoms such as

skipping sensation or palpitations; they are often single

and isolated, but may be frequent or occur in a bigeminal

pattern. In predisposed individuals, PSVCs may trigger sup-

raventricular and, less commonly, ventricular arrhythmias.

In the absence of structural heart disease, thyroid dysfunc-

tion, initiation of sustained arrhythmias and moderate/

severe symptoms, no further evaluation or therapy is

required. If the athlete is asymptomatic, with no cardiac

disease, eligibility is for all sports, without further yearly

clinical assessment.

Atrioventricular Nodal ReciprocatingTachycardiaAtrioventricular nodal reciprocating tachycardia (AVNRT)

is the most common form of paroxysmal supraventricular

tachycardia. It is more prevalent in females, is associated

with palpitations, dizziness, and neck pulsations, and rarely

is associated with structural heart disease.

Rates of tachycardia are often between 140 and

250 per minute. The reentrant circuit comprises the

compact AV node and frequently a perinodal atrial tissue.

AVNRT involves reciprocation between two functionally

and anatomically distinct pathways (fast and slow

pathways). The fast pathway appears to be located near

the His bundle at the Kochs triangle apex, whereas

the slow pathway extends infero-posterior to the compact

AV-node tissue and stretches along the septal margin of

the tricuspid annulus at the level of the coronary sinus.

During typical AVNRT, the fast pathway serves as the

retrograde limb of the circuit, whereas the slow pathway is

the anterograde limb (slowfast AV-node reentry). After

conduction through the slow pathway to the His bundle

and ventricle, brisk conduction back to the atrium

over the fast pathway results in inscription of the shorter

duration (40 ms) P wave during or close to the

QRS complex (less than or equal to 70 ms) often with

a pseudo-r in V1. Less commonly (approximately 510%),

the tachycardia circuit is reversed such that conduction

proceeds anterogradely over the fast pathway and retro-

gradely over the slow pathway (fastslow AV-node reentry,

or atypical AVNRT) producing a long R-P tachycardia.

The P wave, negative in leads III and augmented vector

foot (aVF), is inscribed prior to the QRS. Infrequently,

both limbs of the tachycardia circuit are composed of

slowly conducting tissue (slowslow AV-node reentry),

and the P wave is inscribed after the QRS, producing an

RP interval more tha

encyclopedia of exercise medicine in health and disease (2012) - c

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