Exercise physiology

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 unexplained 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)

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]:

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:

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:

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 unexplained dyspnea".)

The arteriovenous oxygen difference is calculated by the following equation:

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]:

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:

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:

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:

where PiO₂ is the inspired partial pressure of O₂ and RER is the respiratory exchange ratio (VCO₂/VO₂).

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 unexplained 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].

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 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 earlier versions of this topic review.