Exercise Physiology - UpToDate

13/05/2022 13:16 Exercise physiology - UpToDate
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Exercise physiology
Author: David M Systrom, MD, FRCPC
Section Editor: Meredith C McCormack, MD, MHS
Deputy Editor: Paul Dieffenbach, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2022. | This topic last updated: Jul 05, 2021.
INTRODUCTION
Physical exercise requires the coordinated interaction of ventilation, cardiac output, and systemic and pulmonary
blood flow and gas exchange to meet the metabolic demands of contracting muscles, as skeletal muscle metabolism
can rise quickly to 50 times its resting rate during heavy exercise. To preserve cellular oxygenation and acid-base
homeostasis during exercise, metabolic, cardiovascular, and respiratory responses must adapt rapidly to these
dramatic changes in tissue demands.
The normal physiologic response to exercise will be reviewed here. The role of exercise testing to evaluate reduced
exercise tolerance due to dysfunction of the respiratory or cardiovascular systems is discussed separately. (See
"Cardiopulmonary exercise testing in the evaluation of dyspnea" and "Cardiopulmonary exercise testing in
cardiovascular disease" and "Exercise ECG testing: Performing the test and interpreting the ECG results" and
"Approach to the patient with dyspnea" and "Prognostic features of stress testing in patients with known or suspected
coronary disease".)
DEFINITIONS
Minute ventilation – Volume of air exhaled per minute, VE
Oxygen uptake (L/min) – VO2
Maximum oxygen uptake – VO2max defined as inability to increment VO2 despite increasing workload, which is
distinct from "peak VO2," which is the highest recorded VO2 value in the absence of a plateau
Oxygen consumption in tissues (eg, muscle) – QO2
Carbon dioxide output from lungs (L/min) – VCO2
Carbon dioxide production in tissues – QCO2
Arterial oxygen content – CaO2
Mixed venous oxygen content – CvO2
Respiratory exchange ratio (RER) – VCO2/VO2 (measured at the mouth)
Lactate threshold (LT) – The level of oxygen uptake in the lungs (VO2) at which a sustained rise in blood lactate above
resting concentrations occurs
Ventilatory threshold – The point during exercise at which the VCO2 increases out of proportion to the VO2, which is
approximately the same point as the LT
Breathing reserve index – Ratio of VE at peak exercise (VEmax) to maximal voluntary ventilation (MVV)
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Aerobic efficiency – VO2/work, the amount of oxygen uptake in the lungs for a given amount of work performed
(watts) typically measured as a slope during incremental exercise.
ORGAN SYSTEM-SPECIFIC ROLES IN EXERCISE PERFORMANCE
The integrated function of several systems (ie, skeletal muscle, energy supply, cardiac output, circulation, respiration)
is necessary for a normal response to physical exercise. The contribution of each of these systems is outlined in the
following sections.
Skeletal muscle — Skeletal muscles are organized in motor units, composed of between 10 and 2000 muscle fibers.
Each motor unit is innervated by a single motor neuron. The muscle fibers within a given motor unit are classified as
type I or type II based on features such as the oxidative or glycolytic enzyme content, contraction speed, myoglobin
content, and myosin adenosine triphosphatase content ( table 1) [1,2]. These features in turn influence the
mechanical output of the muscle unit.
Type I (also called red or slow-twitch) fibers have a high content of the oxygen binding protein myoglobin, a high
content of oxidative enzymes for producing adenosine triphosphate (ATP), and a high density of mitochondria [2].
These fibers tend to be fatigue resistant and are recruited for low-level endurance activity. The high myoglobin
content in type I fibers provides a ready supply of oxygen for oxidative metabolism.
Type II (also called white or fast-twitch) fibers are further categorized as types IIA and IIX ( table 1) [2]. Type IIA
fibers are similar to type I in their myoglobin content and oxidative enzyme capacity. Type IIX fibers have a low
content of myoglobin and high anaerobic, glycolytic capacity and are recruited for short-term, heavy work,
particularly work above 70 percent of the muscle's aerobic capacity [2].
Fiber type varies considerably among human muscles; as examples, the soleus consists predominantly of type I
fibers, while the triceps is composed mainly of type II fibers, and the vastus lateralis muscle is approximately 50
percent type I. The fiber type mix within a given muscle varies among individuals and is genetically determined.
Training can result in a greater capillary density, increased muscle fiber size, and an increased concentration of
mitochondria within a fiber, along with the potential for alteration of the proportion of fiber types within a given
muscle [2,3]. (See 'Adaptations to training' below.)
Metabolism in skeletal muscles — Muscle contraction and relaxation depend primarily upon hydrolysis of ATP,
which releases the chemical energy necessary for binding of the protein myosin with actin filaments to allow myosin
to slide along the actin filament leading to mechanical contraction. Energy metabolism in muscle and the various
metabolic myopathies are discussed separately. (See "Energy metabolism in muscle".)
Energy sources — The main sources for energy to produce the ATP used by skeletal muscle during exercise are
glycogen, glucose, and free fatty acids with glycogen being the predominant source of energy especially during short
bouts of exercise. Protein is rarely used as an energy source, except during periods of starvation. The specific energy
source used by working muscle for aerobic metabolism depends upon a number of factors including the intensity,
type, and duration of exercise, and also physical conditioning and diet.
Glycogen, glucose, and free fatty acids all provide energy for the creation of ATP, although the amount of ATP
generated depends on the metabolic pathway used. Hydrolysis of ATP by the enzyme actomyosin-ATPase permits
actin-myosin cross-bridge formation and release, with resultant muscular contraction; adenosine diphosphate (ADP)
and phosphate (PO4-) are released in the process.
Metabolic pathways — A number of biochemical processes in muscle fibers are responsible for maintaining a
constant supply of ATP, as intracellular stores of the high-energy compound ATP are small and must be continually
replenished. The three main energy producing pathways that are utilized to prevent significant decreases in ATP
concentration during dynamic exercise are the phosphocreatine shuttle, oxidative phosphorylation, and glycolysis.

Phosphocreatine shuttle — Upon initiation of exercise, the first energy "buffer" is the phosphocreatine (PCr)
shuttle, whereby the enzyme creatine kinase splits a molecule of inorganic phosphate (Pi) from PCr, which then
combines with ADP to yield ATP and creatine (Cr). The shuttle mechanism maintains the ATP concentration in the
proximity of actin-myosin cross-bridging for short duration exertion [4]:
PCr + ADP —> Cr + ATP <—> ADP + Pi
When ATP is utilized for muscle contraction, ADP and PO4- are released. Skeletal muscle PCr concentration has been
shown to decrease and recover with incremental exercise [5,6]. Training and oral loading of carbohydrates or creatine
improve PCr kinetics and exercise performance [5,7,8]. (See 'Metabolic system' below.)
Oxidative phosphorylation — The most efficient skeletal muscle ATP source is the oxidative phosphorylation of
intracellular glycogen and free fatty acids (FFA) in the muscle mitochondrion ( figure 1 and figure 2) [9]. In the
initial steps, pyruvate is produced during the metabolism of glycogen, glucose, or FFA and then converted to acetyl
coenzyme A ( figure 3). Acetyl coenzyme A enters the tricarboxylic acid (TCA) cycle (also known as the citric acid
cycle or Krebs cycle) with resultant generation of nicotinamide adenine dinucleotide (NADH) and flavin adenine
dinucleotide (FADH2). Oxidative phosphorylation occurs when NADH and FADH2 donate electrons to generate
approximately 26 molecules of ATP per molecule of pyruvate.
TCA cycle flux in exercising skeletal muscle increases up to 100-fold during strenuous exercise, with associated
fivefold increases in TCA cycle intermediates, known as the intermediate pool [10,11]. Endurance training has been
associated with TCA intermediate pool expansion at the start of exercise and may contribute to improved energy
provision [11]. Whether TCA intermediate pool expansion is necessary to support increased flux, thereby rendering
the reactions that refill the TCA cycle critical to TCA cycle function, or whether TCA intermediate pool expansion is
simply a pyruvate sink reflecting glycolytic pyruvate production exceeding the rate of oxidation in the TCA cycle,
remains controversial [10].
With more prolonged exercise that depletes the skeletal muscle supplies of carbohydrate and FFA, blood borne
glucose, FFA, and gluconeogenic amino acids (eg, branched chain) become additional sources of energy. The
"gluconeogenic" amino acids can be metabolized to alpha keto acids, and then to glucose, and thereby contribute to
ATP production during exercise, especially when muscle glycogen is depleted [12]. The disadvantage of using amino
acids as an energy source is that they are derived from muscle protein, and protein catabolism eventually leads to
loss of muscle strength.
Glycolysis — Glycolysis is a rapid source of ATP production in which pyruvate derived from glycolysis (
figure 3) is converted to lactate without oxygen, yielding two molecules of ATP. However, glycolysis is less efficient
than oxidative phosphorylation as it produces much less ATP than the approximately 26 that are produced by
oxidative phosphorylation [2,13].
The action of adenylate kinase yields the two adenosine diphosphate molecules needed for the reaction:
Glucose + 2Pi + 2ADP <—> 2 Lactate + 2H2O + 2ATP
Glycolysis results in faster production of ATP than oxidative metabolism but cannot be sustained due to a rapid drop
in muscle cytoplasmic pH, which inhibits further glycolysis [13]. Once excess lactic acid is moved extracellularly to the
blood, it is buffered by bicarbonate, thus producing additional CO2 (in excess of O2 consumption). Lactate is then
transported to the liver and nonexercising muscle where it is converted to pyruvate, which in turn is metabolized to
glucose.
Glycolysis is an important ATP source when the capacity of pyruvate dehydrogenase to metabolize pyruvate through
the TCA cycle is exceeded and pyruvate is oxidized via mass action to lactate [14]. These conditions are fostered by the
rapid glycogenolysis associated with elevated plasma catecholamines during heavy, brief exercise and when there is
an imbalance between mitochondrial oxygen supply and demand during ischemic and hypoxic exercise or at the
onset of intense exercise.

Circulatory system — An essential role of the circulatory system during exercise is to deliver oxygen to the muscles
and move proton equivalents from the muscle to the lungs. This task is accomplished by increases of heart rate and
stroke volume, and decreases in systemic and pulmonary vascular resistance.
Fick Principle — The delivery of oxygen to the muscles by the circulatory system (VO2) is expressed in a
rearrangement of the Fick equation:
VO2 = Qt x (CaO2 - CvO2)
In this equation, Qt is the cardiac output (product of heart rate times stroke volume) and (CaO2 - CvO2) is the systemic
oxygen extraction or the difference in O2 content between arterial and mixed venous blood ( figure 4). Increased
muscle activity during exercise results in increased oxygen extraction in the peripheral circulation. (See "Oxygen
delivery and consumption", section on 'Definitions' and "Cardiopulmonary exercise testing in cardiovascular disease",
section on 'Aerobic parameters' and "Cardiopulmonary exercise testing in the evaluation of dyspnea".)
The arteriovenous oxygen difference is calculated by the following equation:
(CaO2 - CvO2) = 1.34 × hemoglobin concentration × (arterial oxygen saturation – mixed venous oxygen saturation)
Maximal cardiac output, which facilitates transport of oxygen from the alveolus to skeletal muscle, determines the
maximal oxygen uptake (VO2 max) and aerobic capacity to a large degree. Maintenance of CaO2 and depression of
CvO2 during exercise are also circulatory functions, requiring exquisite matching of blood flow to ventilation and
tissue metabolism, respectively.
Cardiac output — Cardiac output increases during incremental exercise through changes in both heart rate (HR)
and stroke volume (SV). The relative increments in each component of cardiac output (HR, SV) and C(a-v)O2 that
permit an increase in VO2 during exercise are illustrated in the figure ( figure 5). In healthy adults, cardiac output is
generally the limiting factor in the VO2 max.
● Maximal heart rate – The maximal HR decreases as a function of age, as predicted by the following equation
[15]:
Maximal HR = 220 - age (in years)
However, a meta-analysis of 18,712 subjects found that this equation underestimates the maximal heart rate in
older subjects [16]. The following equation was more accurate for predicting maximal HR in healthy adults:
Maximal HR = 208 - 0.7 x age (in years)
Normally, the difference between achieved and maximal predicted HR (called the heart rate reserve) is less than
15 beats per minute [17].
During incremental exercise, the rise in HR is relatively linear versus VO2, initially due to withdrawal of vagal
tone, and subsequently due to increased sympathetic activity [18]. The maximal HR also appears directly related
to lean body mass [19]. Thus, the malnourished or myopathic patient may have a reduced heart rate (versus the
normal individual) at peak exercise. Training results in a lower HR at rest and at any given VO2 ( figure 6), but
does not affect maximal HR [20]. (See 'Cardiovascular adaptations' below.)
● Stroke volume – Stroke volume (SV) increases in a hyperbolic fashion versus VO2, and maximum values typically
increase by <50 percent in untrained individuals, making SV the least dynamic of the variables in the Fick
equation. However, SV can be augmented by up to 100 percent with training [2,21]. The rise in SV during
exercise is mediated in part by increased contractility, reflected by an increase in left ventricular ejection fraction
(LVEF) of approximately 5 to 10 percent from rest to peak exercise [22]. LV filling is enhanced during exercise by
capacitance venoconstriction, greater negative intrathoracic pressures, and the pumping action of exercising
limbs [23]. As a result, left ventricular end-diastolic volume (LVEDV) also increases by 20 to 40 percent,

augmenting SV by the Frank-Starling mechanism [24]. (See "Pathophysiology of heart failure with reduced
ejection fraction: Hemodynamic alterations and remodeling".)
In a heart with normal relaxation (lusitropic) properties, LV end-diastolic pressure increases to approximately 20
mmHg during maximum exercise [25]. Diastolic filling is limited by the physical constraints of the pericardium,
as evidenced by the increase in maximum cardiac output and VO2 following pericardiectomy [26].
● Maximum cardiac output – Cardiac output normally increases by approximately 5 mL/min for every 1 mL/min
increase in VO2 [27]. This slope is not altered by training, but maximum cardiac output improves with
conditioning to four to five times resting values (up to levels of approximately 25 L/min in a young healthy
individual). Maximum cardiac outputs above 40 L/min have been reported in elite athletes, and elite athletes
may exhaust their breathing reserve before attaining maximal cardiac output [28].
● Abnormal cardiovascular reserve function – Exercise-induced elevations in left sided filling pressures (ie,
exercise pulmonary capillary wedge pressure [PCWP]) can unmask heart failure with preserved ejection fraction
(HFpEF) [15,29]. Cardiac contractility may be relatively preserved at rest in HFpEF, despite dramatic limitations in
the ability to augment systolic and vascular function with the stress of exercise. This is termed abnormal
cardiovascular reserve function [30]. Abnormal endothelium-dependent vasodilation contributes importantly to
vascular stiffening and to abnormal flow-dependent vasodilation with exercise, and aortic stiffness is strongly
related to abnormal exercise capacity in HFpEF patients [31,32]. In a small cohort of patients with HFpEF,
exercise capacity was markedly reduced, related to an inability to increase cardiac output by enhancing preload
(end diastolic volume) [33]. Invasive hemodynamic studies suggest the elevated left-sided filling pressures
compromise exercise capacity through a reduction in cardiac output. A pooled analysis of 910 patients with
HFpEF confirmed that among exercise reserve parameters, the greatest level of impairment is due to an
exaggerated increase in PCWP and abnormal chronotropic response [34], though multiple mechanisms of
exercise intolerance often coexist in HFpEF [35].
To avoid reliance on a single threshold value for abnormal PCWP values in individuals who achieve differential
maximum exercise intensity, PCWP changes during incremental exercise can be indexed to cardiac output
augmentation. Normal values for PCWP/cardiac output slope are <2 mmHg/L/minute. PCWP/cardiac output slope
values in excess of 2 mmHg/L/minute are present in patients with established heart failure and predict future overt
heart failure in patients with normal resting filling pressures [29]. PCWP normally increases about 1.4 mmHg for every
1 mmHg increase in right atrial pressure, suggesting interdependence of right and left ventricular filling [36]. (See
"Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)
Systemic circulation — Several changes occur in the systemic circulation to enhance O2 delivery to the exercising
muscles. Systolic blood pressure (BP) increases via the muscle chemoreflex during exercise, but diastolic pressure
generally remains near resting values [23,37,38]. The rise in mean systemic BP with exertion is normally much less
than the increment in cardiac output, reflecting a decrease in systemic vascular resistance (SVR) [37]. The ability to
decrease SVR has been correlated with exercise performance [39] while an exaggerated blood pressure increment
with exercise predicts future cardiovascular disease in community cohorts, even after adjusting for resting blood
pressure [40].
Blood flow during exercise is preferentially directed to working muscle and away from less metabolically active tissues
such as gut and kidney ( table 2) [27]. Distribution of blood flow is influenced by sympathetic arterial
vasoconstriction and skeletal muscle vasodilation due to local decreases in pH and PaO2, and local increases in
potassium, adenosine, and nitric oxide (NO) [41,42]. Systemic vasodilation by endogenous NO is enhanced by training
[43].
Normal peripheral vasoregulation and a rightward shift (decreased oxygen affinity) of the oxyhemoglobin
dissociation curve with acidosis increase skeletal muscle oxygen extraction, yielding a femoral venous PO2 near 27
mmHg and a systemic O2 extraction ratio ([CaO2 - CvO2] ÷ CaO2) as high as 0.75 ( figure 7) [44-46]. By
comparison, a normal resting systemic O2 extraction rate is approximately 0.25 to 0.30 (see "Oxygen delivery and

consumption", section on 'Oxygen extraction'). As a result, systemic O2 extraction is highly dynamic during exercise
and plays an important, often underappreciated role in determining overall exercise capacity as quantified by peak
VO2 ( figure 5).
Pulmonary circulation — The pulmonary circulation normally receives >95 percent of the cardiac output, and does
so with minimal resistance [24]. Similar to the systemic circulation, the pressure gradient across the pulmonary
vascular bed increases during exercise by a smaller factor than the increase in blood flow due to a fall in pulmonary
vascular resistance (PVR). The decrease in PVR during exercise is a consequence of passive distention of a compliant
circulation, active vasodilation mediated in part by NO, and an increase in cardiac output by up to five times baseline
[47]. A study of young and old normal subjects has redefined upper limits of normal for pulmonary arterial pressure,
resistance, compliance, and capillary wedge pressure [15].
In a study of 406 subjects undergoing cardiopulmonary exercise testing (CPET) for evaluation of dyspnea, continuous
hemodynamic monitoring demonstrated that exercise pulmonary hypertension (ePH), defined as an exercise mean
pulmonary artery pressure (PAP) >30 mmHg, a pulmonary capillary wedge pressure <20 mmHg, and failure of
pulmonary vascular resistance (PVR) to fall below 80 dynes-sec-cm-5, was associated with poor exercise tolerance [48].
These data support the hypothesis that adequate pulmonary vasodilation is critical to enable the thin walled right
ventricle to augment cardiac output during exercise. Exercise-related pulmonary hypertension may unmask the early
diagnosis of pulmonary arterial hypertension [49]. (See "Clinical features and diagnosis of pulmonary hypertension of
unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)
Respiratory system — One of the most remarkable aspects of exercise physiology is the maintenance of arterial
oxygen and carbon dioxide levels (PaO2, PaCO2) within narrow ranges in the face of the large, rapid increases in
metabolic rate that characterize vigorous exertion. These indices are preserved largely because of adaptations in
ventilation and ventilation/perfusion matching.
Ventilation — The minute ventilation (VE), defined as the volume of air that is exhaled (or inhaled) in one minute,
normally rises during incremental exercise as a result of a linear increase in breathing frequency (up to about 50
breaths/minute in normal adults) and a hyperbolic increase in tidal volume (VT, the volume of air inhaled per breath)
[50]. VT reaches a plateau at approximately 50 percent of the resting vital capacity, above which the elastic work of
breathing is prohibitive [51]. Overall, VE can increase approximately 10-fold with intense exertion.
Regulation of ventilation — The mechanisms by which VE is regulated during exercise are incompletely

understood. As an example, the increase in VE during submaximal exercise perfectly matches carbon dioxide
production without any detectable antecedent changes in arterial pH or PaCO2 to initiate the process. Lactic acidemic
stimulation of the carotid bodies has been proposed to drive ventilation during intense exercise, but patients with
McArdle's syndrome regulate ventilation normally during exercise despite minimal lactate production [52]. The
observation that denervation of the carotid bodies in dogs actually increases the exercise ventilatory response
provides further evidence that the chemoreceptors may not be necessary for the hyperpnea of heavy exercise [53].
(See "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)".)
Functional magnetic resonance imaging studies of the human central nervous system suggest that stimuli for
autonomic ventilatory control are integrated in the ventrolateral medulla [54]. A feed-forward locomotor-linked
mechanism emanating from the hypothalamus is capable of stimulating both ventilation and exercise motion in
parallel [55]. In addition, a muscle chemoreflex, stimulated by the local accumulation of metabolic products of
exercise, can also drive ventilation during exercise [56,57]. (See "Control of ventilation".)
Ventilatory threshold — The ventilatory threshold is defined as the point at which the VE increases out of
proportion to the VO2. The ventilatory threshold occurs at approximately the same time as the patient approaches the
lactate threshold (LT, the level of VO2 at which a sustained rise in blood lactate occurs) and metabolic acidemia
ensues. The ventilatory threshold can be used as a noninvasive marker of the LT because these two events normally
occur at a nearly identical level of exercise [58]. (See 'Lactate threshold' below.)

The ventilatory threshold is best demonstrated by plotting VE/VO2 and VE/VCO2 on a graph versus exercise intensity
or stage, where VCO2 is the volume of CO2 produced (L/min). The ventilatory threshold is the point just before
VE/VO2 begins to rise without a similar rise in VE/VCO2 ( figure 8). A simultaneous upward divergence of the slope
of VCO2 relative to VO2 can also be used to localize the ventilatory threshold (termed the V-slope method).
Breathing reserve index — The ratio of VE at peak exercise (VEmax) to the maximal voluntary ventilation (MVV)
at rest has been termed the breathing reserve index (BRI) [2,59,60]. To calculate the BRI, the maximal voluntary
ventilation can either be measured by a 12-second voluntary effort or estimated by multiplying the FEV1 by 40 [61-63].
(See "Overview of pulmonary function testing in adults".)
A BRI (VEmax/MVV) of 0.70 can be sustained for 15 minutes in normal individuals, but values above 0.75 are usually
not attained even at peak exercise in untrained individuals [64]. This observation suggests that VO2 max in normal
individuals is limited by cardiac factors, not ventilation [65,66].
Elite athletes may reach such a high level of cardiovascular fitness that a pulmonary mechanical limitation to exercise
is approached, but this is distinctly unusual [28].
Patients with parenchymal lung disease typically have a low BRI.
Carbon dioxide elimination — For normal individuals, ventilation is regulated to maintain the arterial partial
pressure of carbon dioxide (PaCO2) at isocapnic (constant PaCO2) levels by increasing or decreasing VCO2. When
exercise intensity surpasses aerobic capacity leading to anaerobic glycolysis, respiratory compensation for metabolic
acidosis occurs, and the increased VCO2 results in a decrease in PaCO2 [50,67]. Maximum exercise produces a partially
compensated metabolic acidosis, with an arterial pH of 7.20 to 7.30 [68,69], while short-term exercise to exhaustion
can reduce the arterial pH to 7.15 or less [70]. (See 'Glycolysis' above.)
Elimination of carbon dioxide in the lungs (VCO2) is achieved by increased alveolar ventilation. Alveolar ventilation
reflects the component of tidal volume (VT) that participates in gas exchange; dead-space ventilation (VD) refers to
that component of VT that helps move air to and from alveoli, but does not participate in gas exchange. Increased
alveolar ventilation is associated with a decrease in VD/VT.
Anatomic dead space increases during exercise because of a tethering effect on conducting airways at high VT,
whereas alveolar dead space decreases because of augmented blood flow to the lung apices, giving the net effect of
a slight increase in total (physiologic) VD. However, this effect is more than offset by the increased VT, which produces
a decrease in upright VD/VT from up to 0.45 at rest to less than 0.29 at maximum exercise [2].
The relationship between ventilation and CO2 elimination during exercise is described by the alveolar ventilation
equation:
VE = (863 x VCO2)/PaCO2 (1-VD/VT)
From this equation, the amount of ventilation required for exercise is defined by three factors:
● Carbon dioxide output (VCO2)
● The set point at which PaCO2 is regulated by ventilatory control mechanisms
● The ratio of physiologic dead-space (VD) to VT, or VD/VT
The amount of ventilation required for the lungs to eliminate CO2, expressed as the ratio of VE/VCO2 at the anaerobic
threshold, or the slope of VE/VCO2 during exercise, has been termed "ventilatory efficiency." In normal individuals,
VE/VCO2 does not differ between men and women, but does increase with age. CO2 elimination by the lungs becomes
more efficient during exercise [67].
Impaired ventilatory efficiency (ie, VE/VCO2 slope >28 or VE/VCO2 at anaerobic threshold [AT] >36) is increasingly
recognized as an important determinant of prognosis in disease states associated with increased VD/VT such as

pulmonary arterial hypertension and heart failure ( figure 9) [71]. In patients with heart failure VE/VCO2 slope
elevation correlates with pulmonary vascular resistance and reduction in right ventricular ejection fraction during
exercise [72]. In pulmonary arterial hypertension VE/VCO2 slope decreases, reflecting improved ventilatory efficiency,
in response to pulmonary vasodilator therapy. Hence, VE/VCO2 slope is a potentially attractive surrogate for right
ventricular-pulmonary vascular reserve capacity in patients with suspected heart failure or pulmonary hypertension.
Oxygenation — During exercise, the partial pressure of oxygen in arterial blood (PaO2) remains near resting values
despite marked reductions in mixed venous oxygen tension (PvO2) and an abbreviated red cell transit time through
the pulmonary capillaries. Arterial oxygenation is maintained by several adaptations, including increased alveolar
oxygen tension (PAO2), a decreased number of low V/Q units, increased surface area for O2 diffusion, and a smaller
right-to-left shunt fraction.
The driving pressure for O2 diffusion across the alveolar-capillary membrane is the PAO2, as described by the
equation:
PAO2 = PiO2 - (PACO2 ÷ RER)
where PiO2 is the inspired partial pressure of O2 and RER is the respiratory exchange ratio (VO2/VCO2).
PAO2 increases in normal persons exercising above the lactate threshold at sea level because of hyperventilation
(which lowers PACO2) and an increased RER, due to bicarbonate buffering of lactic acid and "non-metabolic" CO2
production. The excess CO2 is often referred to as "non-metabolic" because it is not produced by metabolism, per se.
Oxygenation also improves in the lung with exercise because of a decrease in the number of low-
ventilation/perfusion units at the bases due to larger tidal breaths. Improved distribution of pulmonary blood flow
also results in augmentation of the diffusing surface area at high cardiac output. Finally, in a manner analogous to
VD/VT, the right-to-left shunt fraction (shunted blood flow relative to total blood flow: Qs/Qt) falls because of the large
increase in Qt.
Some well-trained individuals manifest arterial O2 desaturation at extremely high metabolic rates. This has been
attributed to reduced compensatory hyperventilation and a diffusion limitation resulting from rapid red cell transit
time through the pulmonary capillaries [73,74].
Hematologic contribution — The oxygen carrying capacity of blood (amount of oxygen bound to hemoglobin plus
the amount of oxygen dissolved in arterial blood) is a significant contributor to exercise capacity. Therefore,
hemoglobin level should be taken into account when interpreting cardiopulmonary exercise test results. (See
"Oxygen delivery and consumption".)
ASSESSMENT OF EXERCISE CAPACITY
Cardiopulmonary exercise testing (also known as multiparameter exercise testing) yields detailed information on an
individual's response to exercise [2,75]. The symptom-limited, incremental exercise test involves a continuous,
ramped increase in workload that continues until the patient has symptoms (eg, dyspnea, fatigue) that cause the
patient to feel unable to exercise at a higher workload. Physiologic data, including oxygen uptake, carbon dioxide
output, tidal volume, minute ventilation, electrocardiographic (ECG) tracings, and pulse oximetry are measured
throughout the test and during the first several minutes of recovery. (See "Cardiopulmonary exercise testing in the
evaluation of dyspnea" and "Cardiopulmonary exercise testing in cardiovascular disease" and "Exercise capacity and
VO2 in heart failure".)
Invasive cardiopulmonary exercise testing, which adds radial and pulmonary artery catheter pressure and blood gas
measurements to the noninvasive test, has been used to better understand physiology and complex disorders of the
heart, lung, and skeletal muscle [15,33,76-79].

Maximum oxygen uptake — The maximum oxygen uptake (VO2 max, L/minute) reflects the maximal ability of a
person to take in, transport, and use oxygen, and it defines that person's functional aerobic capacity. VO2 max has
become the "gold standard" laboratory measure of cardiorespiratory fitness and is the most important parameter
measured during functional exercise testing. The VO2 max attained during incremental bilateral leg exercise (eg,
bicycle ergometer, treadmill) is used to provide an overall assessment of exercise capacity [80-83]. VO2 increases
linearly versus work rate with a slope of approximately 10 mL/min per watt in normal subjects [68]. This slope is not
affected by age, sex, or training but is shifted leftward in obese patients ( figure 10).
A true VO2 max is identified by a plateau of VO2 when VO2 is graphed versus work, but this plateau occurs only in a
subset of normal subjects and patients, usually during a maximal incremental protocol [83]. In cases where VO2 max
is not achieved, peak VO2, averaged over the highest values during 30 of the final 60 seconds of exercise, is the more
appropriate term to describe the highest achieved oxygen uptake during exercise.
VO2 max is often indexed to body weight (mL/kg per min) or expressed in metabolic equivalents (METS), which are
multiples of normal baseline oxygen uptake at rest. One metabolic equivalent (MET) is equal to 3.5 mL/kg/min.
Normal reference values have been reported from a population-based survey in which rigorous phenotyping was
used to limit analyses to healthy individuals ( table 3) [84]. These values, derived with cycle ergometry, are
complemented by modern normative values derived from 7783 healthy individuals who completed treadmill testing
in the Fitness Registry and the Importance of Exercise Consortium [85].
VO2 max (ml/kg/min) = 79.9 – (0.39 x age [years]) – (13.7 x sex (0=male, 1=female) – (0.127 x weight [lbs])
These values replace previous values derived from male shipyard workers [68], university members [86], and soldiers
[87].
Of note, VO2 max achieved during cycle ergometry, as illustrated in the table ( table 3), is 5 to 11 percent lower than
that achieved during exercise treadmill testing, due to lower muscle mass utilized during cycle ergometry [88,89].
A normal VO2 max usually exonerates the pulmonary, cardiovascular, and neuromuscular systems of serious
pathology, although intra- or inter-organ compensation for mild primary abnormalities can result in a relatively
normal value. As an example, patients with chronotropic disturbances of the heart provide an example of intra-organ
compensation; near-normal values for cardiac output may be preserved during exercise by relative increases in stroke
volume, via the Frank-Starling mechanism [80]. Examples of inter-organ compensation include the elevation in
cardiac output commonly seen in anemic individuals [90], and the improvement in systemic O2 extraction which
occurs in some patients with cardiac dysfunction [91] as slower transit time in the periphery permits greater diffusive
conduction of oxygen.
Maximum work — The maximum work (in watts; 1 watt equals 0.0143 kcal/min) achieved during an incremental
exercise test has been used to evaluate overall exercise capacity. However, this variable can be misleading because a
significant amount of work can be performed by obese patients and those with obstructive airways disease beyond
that which is measured by the cycle ergometer or treadmill [75,92]. As an example, the work of breathing in
obstructive airways disease may be substantial. In such a situation, a low maximum external work rate may be
recorded even though the more meaningful value of VO2 max is relatively normal.
Lactate threshold — Heavy workloads are associated with an increase in blood lactate concentration, although the
specific workload that results in an increase in lactate concentration varies from one individual to another (
figure 11). The level of oxygen uptake in the lungs (VO2) at which a sustained rise in blood lactate occurs is called
the lactate threshold (LT). The anaerobic threshold is the level of VO2 above which glycolytically produced ATP
supplements aerobic ATP production, and both the blood level of lactate and the ratio of lactate to pyruvate increase.
Practically speaking these metabolic events occur together. (See 'Glycolysis' above.)
For many years the lactic acidemia of exercise was assumed to be secondary to inadequate oxygen (O2) delivery to
muscle with resultant increases in anaerobic glycolysis to produce ATP. However, since the 1980s, it has been

appreciated that the skeletal muscle mitochondrial redox state is actually higher when working muscle is producing
lactate than at rest, implying that oxygen supply is not the critical factor [14,93,94]. Currently, the LT is considered to
be the VO2 at which pyruvate, and therefore lactate, production exceeds its ability to be metabolized via the TCA cycle
[14].
At a VO2 just below LT, steady state metabolic conditions remain preserved, and exercise can be sustained for
prolonged periods [95]. The LT varies with cardiovascular fitness and is a useful clinical index [17,18].
The LT occurs at greater than 40 percent of the predicted VO2 max in normal individuals but earlier in the course of
exercise among patients with cardiovascular disease [19,20]. (See "Exercise capacity and VO2 in heart failure".)
Exercise intensity must approach the LT for optimal training effects to occur [96]. An endurance athlete will not reach
an LT until 80 to 90 percent of the VO2 max and usually competes at a metabolic rate just below the LT.
Fatigue — Fatigue during exercise has both central (nervous system) and peripheral (muscle) components, of which
the latter is better understood [97,98]. The development of peripheral fatigue depends upon the intensity and
duration of exercise and is influenced by:
● Accumulation of metabolic byproducts

● Depletion of high-energy phosphates
● Depletion of glycogen substrate
During brief, intense exercise, skeletal muscle intracellular pH decreases because of the accumulation of cytosolic
lactate and loss of potassium [99]. Increased concentration of hydrogen ion in the myocyte may contribute to fatigue
through inhibition of glucosyl flux and muscle contraction [70,100]. With acute exercise to exhaustion, for example,
the intracellular lactate concentration can exceed 40 meq/L and the pH may fall below 6.40 [101].
Ammonia, generated from deamination of AMP to inosine monophosphate in the stressed type II muscle fiber, has
also been implicated in peripheral fatigue, possibly via inhibition of oxidative phosphorylation [102]. Training is
associated with relatively less ammonia and lactate in muscle and blood during exercise and with less fatigue at a
given metabolic rate [98,103].
Depletion of high-energy phosphate compounds also probably plays a role in peripheral fatigue with short-term
exercise [5]. Evidence for the importance of this phenomenon is provided by patients with McArdle's disease, who are
incapable of producing significant quantities of lactate but who fatigue quickly during exercise [104]. In contrast,
fatigue during endurance events appears related to the depletion of glycogen stores rather than high-energy
phosphates. This is thought to be responsible for the phenomenon of the marathon runner "hitting the wall." Muscle
metabolism rarely is the critical factor in determining maximal exercise tolerance, but it may affect an individual's
ability to sustain high levels of exertion [93]. (See 'Metabolic system' below.)
ADAPTATIONS TO TRAINING
Long-term adaptations to exercise training include effects upon the musculoskeletal, metabolic, cardiovascular, and
respiratory systems. The improvements in muscle and cardiorespiratory function with endurance training increase
the maximal oxygen uptake (VO2 max) and the lactate threshold [105-109]. Thus, the endurance trained individual can
perform at higher rates of work than an untrained person. (See 'Maximum oxygen uptake' above and 'Ventilatory
threshold' above.)
Musculoskeletal system — Skeletal muscle adapts to regular physical activity training with a variety of changes [2,3].
The type of training (eg, prolonged endurance or resistance) affects the type of muscular adaptations [3]. Endurance
training leads to mitochondrial biogenesis, fast-to-slow fiber transformation, expansion of the muscle capillary bed,
and changes in substrate metabolism. Resistance training typically increases the size of muscle fibers, which leads to
the ability to exert more force [3]. Prolonged and high-intensity exercise has been shown to increase strength and the
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cross sectional area of ligaments and tendons. In general, women and men of all ages show gains in strength from
resistance training, although the degree of adaptation to training varies from one individual to another [110]. Some
individuals have virtually no gain in muscle mass with resistance training, while others experience up to a 60 percent
increase [110]. High-intensity interval training has been shown to achieve many of the benefits of endurance training
with a lower volume of training [111].
Training-related expansion of the muscle capillary bed allows greater blood flow to active muscles and a more
efficient delivery of oxygen and energy sources.
Metabolic system — Metabolic adaptations to endurance training include the following [2,112,113]:
● Increase in the size and number of muscle mitochondria
● Increase in the capacity of skeletal muscle to store glycogen
● Expansion in pool of tricarboxylic cycle intermediates in muscle mitochondria (see 'Oxidative phosphorylation'
above)
● Improvement in fat utilization as an energy source by trained muscles, which spares glycogen stores [114]
Cardiovascular adaptations — Important changes occur in the cardiovascular system in response to endurance

training [115-117]:
● Cardiac muscle fibers hypertrophy, the muscle mass of the ventricles increases, and the force of contraction is
greater.
● Well-trained athletes have substantial enlargement of the left ventricle (LV) to a degree compatible with a
primary dilated cardiomyopathy. However, global left ventricular systolic function is normal and without regional
wall motion abnormalities.
● The total peripheral resistance decreases due to enhanced capillary capacity for blood flow, which improves
oxygen and nutrient delivery to exercising muscles.
The increases in force of myocardial contraction and LV size together enable an increase in stroke volume.
Respiratory adaptations — One of the respiratory adaptations to exercise training is a decrease in minute

ventilation (VE) to achieve a given VO2 or VCO2, although the effects of training are most pronounced at levels of
exercise beyond the lactate threshold. The lower VE observed after training appears to be a function of ventilatory
training rather than changes in the control of respiration. (See 'Respiratory system' above.)
The maximal oxygen uptake during exercise (VO2 max) increases as a function of training [71]. A young, world-class
endurance athlete may have a VO2 max greater than 80 mL/kg per minute. Historically, values in women have been
considered less than those of age-matched men of similar size, but a significant portion of the difference has been
shown to be related to training status [9]. Biomechanical efficiency for running and cycling may be less for women,
but during certain endurance events, enhanced oxidation of fat by women is glycogen-sparing and may be
advantageous [9].
Lactate levels at VO2 max are lower for a given level of work in trained athletes than in sedentary controls. In addition,
endurance training of normal subjects leads to a decrease in blood lactate for a given level of exertion compared with
values prior to training.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Stress testing and cardiopulmonary exercise testing".)

SUMMARY
● Skeletal muscle metabolism can rise quickly up to 50 times its resting rate during heavy exercise. This is
accomplished by increases in minute ventilation, cardiac output, and systemic oxygen extraction along with
microvascular adaptations that increase the delivery of oxygen to the muscles. (See 'Introduction' above.)
● Human skeletal muscles are composed of type I (also called red or slow twitch) fibers and type II (also called
white or fast twitch) fibers ( table 1). Type II fibers are further categorized as types IIA and IIX. For each
individual, the relative proportion of fiber types influences the capacity for the particular type of exercise (eg,
low-level endurance, rapid heavy work). (See 'Skeletal muscle' above.)
● The main energy sources used by skeletal muscles during exercise are glycogen, glucose, and free fatty acids.
Protein is rarely used as an energy source, except during periods of starvation. These substrates provide the
chemical energy to create adenosine triphosphate (ATP), which is used for myosin cross-linking to actin. (See
'Energy sources' above.)
● Upon initiation of exercise, the most immediate source of energy is the phosphocreatine (PCr) shuttle, in which
the enzyme creatine kinase splits a phosphate molecule off PCr, and the phosphate molecule then combines
with adenosine diphosphate to make ATP. ATP is then immediately available to myosin for contraction. (See
'Phosphocreatine shuttle' above.)
● The most efficient source of ATP comes from metabolism glucose and glycogen to pyruvate by glycolysis
followed by metabolism of pyruvate via the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or
Krebs cycle) in the mitochondria. During low-level exercise, the majority of muscle metabolism is aerobic,
meaning that there is adequate oxygen to metabolize pyruvate by oxidative phosphorylation which provides the
maximum amount of ATP. Alternatively, fatty acids or, rarely, protein are metabolized to acetic acid and enter the
TCA cycle. (See 'Energy sources' above and 'Oxidative phosphorylation' above.)
● With progressively increasing muscular work, the capacity of pyruvate dehydrogenase to metabolize pyruvate is
exceeded, and glycolysis becomes the source of ATP ( figure 2). This point is known as the lactate threshold
(LT), or the level of oxygen uptake in the lungs (VO2) at which a sustained rise in blood lactate occurs (
figure 11). Glycolysis metabolizes pyruvate to lactate with a lower yield of ATP than the TCA cycle. (See
'Metabolic pathways' above.)
● The ventilatory threshold is defined as the point at which the minute ventilation (VE) increases out of proportion
to the VO2 ( figure 8) and occurs at approximately the same time as the patient approaches the lactate
threshold (LT). Thus, the ventilatory threshold is sometimes used as a noninvasive marker of the LT. (See 'Lactate
threshold' above and 'Ventilatory threshold' above.)
● The maximal cardiac output normally sets the limit on aerobic exercise capacity, although endurance training
typically leads to increased cardiac output. (See 'Circulatory system' above.)
● The maximum oxygen uptake (VO2 max) reflects the maximal ability of a person to take in, transport, and use
oxygen, and it defines that person's functional aerobic capacity ( figure 10). The VO2 max has become the
"gold standard" laboratory measure of cardiorespiratory fitness and is the most important parameter measured
during functional exercise testing. (See 'Assessment of exercise capacity' above.)
● The LT occurs at above 40 percent of the predicted VO2 max in normal individuals. In comparison, LT occurs
earlier (at a lower percent of VO2 max) in the course of exercise among patients with cardiovascular disease, but
later (at a higher percent of VO2 max) in endurance trained athletes. (See 'Definitions' above and 'Lactate
threshold' above.)
● Training enhances virtually every step of exercise gas exchange from the lung to the skeletal muscle
mitochondrion. Endurance training leads to mitochondrial biogenesis, fast-to-slow fiber transformation,
changes in substrate metabolism, expansion of the muscle capillary bed, and increased cardiac output.
Resistance training typically increases the size and protein content of muscle fibers, which leads to the ability to
exert more force. (See 'Adaptations to training' above.)
● The clinical use of cardiopulmonary exercise testing is discussed separately. (See "Cardiopulmonary exercise
testing in cardiovascular disease" and "Evaluation of pulmonary disability" and "Preoperative physiologic
pulmonary evaluation for lung resection" and "Exercise capacity and VO2 in heart failure".)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Gregory D Lewis, MD, who contributed to an earlier version of this topic
review.
Use of UpToDate is subject to the Terms of Use.
Topic 1433 Version 19.0

GRAPHICS
Muscle fiber characteristics
Type Color Contraction Metabolism Myoglobin content
I Red Slow twitch Oxidative High
IIA Red Fast twitch Fast oxidative High
IIX White Fast twitch Anaerobic glycolysis Low
Reproduced with permission from: Wasserman K, Hansen JE, Sue DY, et al. Physiology of exercise. In: Principles of exercise testing and interpretation:
Including pathophysiology and clinical applications, 5th ed, Lippincott Williams & Wilkins, 2011. Copyright © 2011 Lippincott Williams & Wilkins.
www.lww.com.
Graphic 62260 Version 4.0

Metabolic reactions in the mitochondria
The respiratory chain is composed of 4 multi-subunit complexes (I, II, III, and
IV) linked by the mobile electron carriers coenzyme Q and cytochrome c. The
reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin
adenine dinucleotide (FADH2) are formed from the citric acid cycle and the
beta-oxidation of fatty acids in the mitochondrial matrix. The respiratory chain
transfers electrons from NADH (via complex I) and from reduced flavoproteins
(via complex II and electron transfer flavoprotein-coenzyme Q oxidoreductase
[ETF-Qo]) to coenzyme Q, then complex III, cytochrome c and finally complex
IV. At the same time, complexes I, III, and IV pump electrons across the inner
mitochondrial membrane from the matrix to the intermembrane space. The
influx of these electrons (protons) back into the mitochondrial matrix releases
energy that is used in the phosphorylation of ADP to ATP by complex V (ATP
synthetase), which is also embedded in the inner mitochondrial membrane.

Schem reg glucose metab
Reproduced with permission from: Cryer PE, Polonsky KS. Glucose homeostasis and
hypoglycemia. In: Williams Textbook of Endocrinology, 9th ed, Wilson, JD, Foster, DW,
Kronenberg, HM, Larsen, PR (Eds), WB Saunders Co., Philadelphia 1998. p.940. Copyright
©1998 Elsevier Science.

Metabolic pathways of glycogen metabolism and glycolysis
The figure shows the sites of enzymatic defects resulting in clinical glycogenoses.

The glycogen storage disease types are as follows:
Type 0: Glycogen synthase deficiency
Type Ia: Glucose-6-phosphatase (G6Pase) deficiency or von Gierke disease
Type II: Acid maltase deficiency or Pompe disease
Type III: Glycogen debrancher deficiency
Type IV: Glycogen branching deficiency or Andersen disease
Type V: Muscle phosphorylase deficiency or McArdle disease
Type VI: Liver phosphorylase deficiency or Hers disease
Type VII: Phosphofructokinase (PFK) deficiency or Tarui disease
Type IX: Phosphorylase b kinase (PBK) deficiency
Type X: Phosphoglycerate mutase (PGAM2) deficiency
Type XI: Lactate dehydrogenase (LDH) deficiency
Type XII: Aldolase A deficiency
Type XIII: Beta-enolase deficiency
Type XIV: Phosphoglucomutase-1 (PGM1) deficiency
Other deficiency syndromes, enzymes, and intermediates include the following:
Fructose-1,6-bisphosphatase (F-1,6-BP) deficiency
Glucokinase (GK)
Glucose transporter 2 (GLUT2) deficiency or Fanconi-Bickel syndrome
Phosphoglycerate kinase (PGK) deficiency
Phosphoenolpyruvate carboxykinase (PEPCK) deficiency
Phosphorylase limit dextrin (PLD)
Pyruvate carboxylase (PC) deficiency
Pyruvate dehydrogenase (PDH)
Pyruvate kinase (PK) deficiency
Uridine diphosphoglucose (UDPG)
Uridine diphosphoglucose pyrophosphorylase (UDPG-P)

Adapted from: Griggs R, Mendell J, Miller R. Metabolic myopathies. In: Evaluation and Treatment of
Myopathies, Griggs R, Mendell J, Miller R (Eds), FA Davis Co., Philadelphia 1995. p.247.

Calculation of AV oxygen difference and cardiac output

using the Fick method
Oxygen consumption is estimated from a nomogram based on age, sex,

height, and weight. In addition, oxygen consumption can be measured
directly using exhaled breath analysis.
Hgb: serum hemoglobin (g/dL)
SaO2: arterial oxygen saturation (percent) measured from arterial blood
SvO2: mixed venous oxygen saturation (percent) measured from the

pulmonary artery in the absence of a shunt or calculated using MvO2 = [3
SVC saturation + IVC saturation] divided by 4 if a left to right shunt is
present.
Constant values: 1.34 mL O2 per gram Hgb; 10 dL per L.

Effect of exercise training on oxygen uptake at peak exercise
The left panel illustrates representative normal values for oxygen uptake at rest, at peak exercise, and at
peak exercise following exercise training in a 25-year-old male. The right panel illustrates relative changes in
the three components of VO2 (heart rate, stroke volume, and arteriovenous difference in oxygen content) in
response to maximal exercise.
VO2: oxygen uptake; HR: heart rate; SV: stroke volume; C: content.
Courtesy of Gregory D Lewis, MD.

Heart rate and oxygen consumption during

exercise
Schematic representation of the heart rate - oxygen uptake (VO2)

relationship during incremental exercise in normal (red circles) and
well-trained individuals (blue squares).

Blood flow distribution at rest and at maximal exercise
Rest (percent total) Maximal exercise (percent total)
Splanchnic 24 1
Skeletal muscle 21 88
Kidneys 19 1
Brain 13 3
Skin 8 2
Heart 3 4
Other organs 10 1

Oxyhemoglobin dissociation curve
The oxygen-hemoglobin dissociation curve correlates the oxygen saturation of hemoglobin across a range of oxygen pressures. The
line shows the curve for normal adult hemoglobin (HbA). Notable points on the curve include:
p50 — The p50 is the pressure at which hemoglobin is 50% saturated (27 mmHg on the X-axis).
Arterial blood — Hemoglobin is approximately 100% saturated at an oxygen pressure of 100 mmHg.
Venous blood — Hemoglobin is approximately 75% saturated.

Conditions that shift the curve may affect oxygen delivery to the tissues; these effects are most pronounced at low partial pressures
Left shift — Conditions that shift the curve to the left (dashed red line) increase the oxygen affinity; hemoglobin holds more ti
oxygen and delivers less oxygen to the tissues at a given arterial oxygen pressure. The left-shifted curve for HbF is what allows
oxygen from the maternal to the fetal circulation.
Right shift — Conditions that shift the curve to the right (dashed blue line) decrease oxygen affinity; hemoglobin holds less tig
oxygen and delivers more oxygen to the tissues at a given arterial oxygen pressure.
Hb: hemoglobin; O2: oxygen gas; HbF: fetal hemoglobin; R state: relaxed state of hemoglobin; T state: tense state of hemoglobin.
* The ferric hemes of methemoglobin do not bind oxygen, but they increase the oxygen affinity of the normal ferrous heme in the he
tetramer, shifting the curve left. With high methemoglobin levels, oxygen saturation will be low for a physiologic PaO2 due to inability
heme to bind oxygen, shifting the curve right.

Ventilatory threshold
The ventilatory threshold is the intensity at which ventilation begins

to rise in excess of VO2. It is best demonstrated by plotting VE/VO2
and VE/VCO2 on the same graph (as above). The ventilatory
threshold is the point just before VE/VO2 begins to rise without a
similar rise in VE/VCO2.
VE: volume of gas expired (L/min); VO2: volume of oxygen

consumed (L/min); VCO2: volume of carbon dioxide produced
(L/min).

Ventilatory efficiency predicts risk for major cardiac events
Kaplan-Meier analysis for two-year major cardiac-related events. Subjects meeting criteria
for VC-1 (VE/VCO2 slope ≤29.9; n = 144) experienced four major cardiac events (including
two heart transplants); 97.2% were event-free. Subjects meeting VC-II criteria (VE/VCO2
slope 30 to 35.9; n = 149) experienced 22 major cardiac events (including three LVAD
implantations); 85.2% were event-free. Subjects meeting VC-III criteria (VE/VCO2 slope 36 to
44.9; n = 112) experienced 31 major cardiac events (including three LVAD implantations and
two heart transplants); 72.3% were event-free. Subjects who met VC-IV criteria (VE/VCO2
slope ≥45; n = 43) experienced 24 major cardiac events (including two LAVD implantations
and five heart transplants); 44.2% were event-free. Log-rank 86.8, p<0.0001.
VE: minute ventilation; VCO2: carbon dioxide output; LVAD: left ventricular assist device.
From: Arena R, Myers J, Abella J, et al. Development of a ventilatory classification system in patients with heart
failure. Circulation 2007; 115:2410. Reproduced with permission from Lippincott Williams & Wilkins. Copyright ©
2006 American Heart Society. Unauthorized reproduction of this material is prohibited.

Oxygen consumption and workload during exercise
Schematic representation of the normal VO2-workload relationship

during incremental exercise to exhaustion (blue circles). The
relationship is left-shifted for obese individuals (red triangles).

Normal values for maximum oxygen uptake during cycle ergometry
Age 25-34 35-44 45-54 55-64 >64
Men
Median VO2 38
36
35
33
30
max (26-51) (24-48) (23-45) (20-40) (17-36)

(mL/minute per
kg)
(5th -95th
percentile)
Women
Median VO2 30
29
27
25
22
max (22-41) (21-39) (20-37) (18-32) (16-28)

(mL/minute per
kg)
(5th -95th
percentile)
Normal VO2 max values, based on incremental bicycle ergometry testing in healthy individuals derived from a population-
based cohort.
VO2 max: maximum oxygen uptake during exercise.
Data from: Koch B, Schaper C, Ittermann T, et al. Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study. Eur Respir J
2009; 33:389.

Lactate threshold during exercise
Schematic representation of the normal blood lactate - oxygen

uptake (VO2) relationship during incremental exercise. The lactate
threshold (LT) denotes the onset of a sustained rise in blood lactate.


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13/05/2022 13:16 Exercise physiology - UpToDate

Official reprint from UpToDate®

Minute ventilation – Volume of air exhaled per minute, VE

Oxygen uptake (L/min) – VO2

Oxygen consumption in tissues (eg, muscle) – QO2

Carbon dioxide output from lungs (L/min) – VCO2

Carbon dioxide production in tissues – QCO2

Arterial oxygen content – CaO2

Mixed venous oxygen content – CvO2

Respiratory exchange ratio (RER) – VCO2/VO2 (measured at the mouth)

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ORGAN SYSTEM-SPECIFIC ROLES IN EXERCISE PERFORMANCE

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PCr + ADP —> Cr + ATP <—> ADP + Pi

Glucose + 2Pi + 2ADP <—> 2 Lactate + 2H2O + 2ATP

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VO2 = Qt x (CaO2 - CvO2)

The arteriovenous oxygen difference is calculated by the following equation:

Maximal HR = 220 - age (in years)

Maximal HR = 208 - 0.7 x age (in years)

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Regulation of ventilation — The mechanisms by which VE is regulated during exercise are incompletely

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Patients with parenchymal lung disease typically have a low BRI.

VE = (863 x VCO2)/PaCO2 (1-VD/VT)

● Carbon dioxide output (VCO2)

● The set point at which PaCO2 is regulated by ventilatory control mechanisms

● The ratio of physiologic dead-space (VD) to VT, or VD/VT

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PAO2 = PiO2 - (PACO2 ÷ RER)

ASSESSMENT OF EXERCISE CAPACITY

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● Accumulation of metabolic byproducts

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Metabolic system — Metabolic adaptations to endurance training include the following [2,112,113]:

● Increase in the size and number of muscle mitochondria

● Increase in the capacity of skeletal muscle to store glycogen

Cardiovascular adaptations — Important changes occur in the cardiovascular system in response to endurance

Respiratory adaptations — One of the respiratory adaptations to exercise training is a decrease in minute

SOCIETY GUIDELINE LINKS

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Use of UpToDate is subject to the Terms of Use.

Topic 1433 Version 19.0

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Muscle fiber characteristics

Type Color Contraction Metabolism Myoglobin content

I Red Slow twitch Oxidative High

IIA Red Fast twitch Fast oxidative High

IIX White Fast twitch Anaerobic glycolysis Low

Graphic 62260 Version 4.0

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Metabolic reactions in the mitochondria

Graphic 67253 Version 11.0

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Schem reg glucose metab

Graphic 82039 Version 2.0

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Metabolic pathways of glycogen metabolism and glycolysis