Exercise Physiology
Exercise produces significant increases in the body's demand for energy compared to its resting state. While at rest, the autonomic nervous system tends to favor a parasympathetic tone, which reduces the respiratory and heart rate. The sympathetic nervous system is activated during exercise, resulting in an integrated response that helps maintain an appropriate level of homeostasis to meet the increased demand in cellular metabolism.[1]
Cardiovascular disease continues to be a prevalent issue in our patient population despite advances in prevention guidelines and treatments. The top risk factors include hypercholesterolemia, hypertension, diabetes, obesity, and tobacco use. These mentioned risk factors encompass nearly 50% of the mortality fraction. The lack of exercise tends to worsen the negative effects of these risk factors. On the other hand, daily exercise has been shown to reduce mortality rates. Additionally, lack of exercise is directly linked to obesity, type 2 diabetes, and hypertension.[2]
Research has demonstrated that exercise, along with other lifestyle modifications, can reduce the risk of hypertension, regardless of inherent genetic predispositions. Furthermore, exercise has been shown to increase insulin sensitivity in diabetes management.[3]
Attaining a healthy body weight can reduce cardiovascular disease mortality. Exercise is a noninvasive and nonpharmaceutical intervention that improves quality of life.
The skeletal muscle plays a crucial role in body movement and regulating metabolism. The sarcomere, which is the fundamental unit of the skeletal muscle, is critical for contraction. The sarcomere consists of contractile proteins that are organized into thick and thin filaments. Myosin, a protein that interacts with actin and adenosine triphosphate (ATP), is the main component of the thick filaments. The thin filaments are composed of actin monomers that form a tight helix. Tropomyosin is a 2-stranded actin-associated protein that lies along the major groove of actin filaments. This protein regulates the access of the troponin complex to actin. The troponin complex is located between the actin filaments and consists of 3 subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT).[4]
Intracellular calcium is released from the sarcoplasmic reticulum upon electrical stimulation of the muscle. Calcium binds to TnC, causing a conformational change that triggers structural alterations in TnT and tropomyosin. These interactions among tropomyosin, the troponin complex, and calcium regulate muscle contraction. Consequently, the myofilament becomes activated, enabling force generation.[5]
ATP-driven pumps extract calcium from the sarcoplasm back into the sarcoplasmic reticulum to relax from the contractile state, leading to the reshielding of the actin-binding sites on the thin filaments. This mechanism releases the actin site with a return to the high-energy state of myosin. This shortening-and-lengthening model may be explained by the sliding filament theory, which states that actin and myosin filaments slide past each other to shorten the length of the sarcomere.[6]
Movement requires a coordinated response of multiple organ systems. When the body engages in regular physical activity, all physiologic systems undergo specific adaptations to increase movement efficiency and exercise capacity.
Musculoskeletal System
Muscular adaptations to exercise involve changes in muscle fiber composition and function driven by the specific demands of physical activity. These adaptations, alongside skeletal responses such as increased bone mineral density, are essential for optimizing training strategies, enhancing athletic performance, and promoting long-term musculoskeletal health.
Muscular adaptations to exercise
The musculoskeletal system is responsible for regulating the strength, speed, and coordination required to perform physical tasks. Muscle fibers may be classified based on their myosin heavy chain isoforms, which determine their shortening velocities, or by their oxidative capacity, which relates to their metabolism and fatigability.[7]
The composition of a subject's muscle fibers can impact sports performance. Individuals with a higher proportion of type I fibers tend to excel in longer-duration events. In contrast, individuals with more type II fibers generally perform better in shorter, higher-speed events. Training at slower speeds with higher loads can result in a shift from IIx and IIx/IIa hybrids to a more pure IIa phenotype, with minimal change in the pure Ia phenotype. Conversely, high-speed, high-power training can reduce type Ia fibers and produce a shift toward the faster IIx/IIa phenotype.
Muscle contraction initiates movement by acting on the skeleton. Muscles adapt to increasing loads over time through exercise training, resulting in muscle fiber hypertrophy and increased muscle diameter and volume. Satellite cells are positioned on the outer edge of muscle fibers closely linked to the plasma membrane. These myogenic precursors are essential for supporting the development of skeletal muscle fiber adaptations to loading. These cells also play a vital role in muscle hypertrophy and repair. Exercise, whether through long-distance running or powerlifting, stresses the muscle fibers and bones, causing microtears that activate and mobilize satellite cells to regenerate the damaged muscle tissue.[10][11]
Skeletal adaptations to exercise
Bone remodeling occurs in response to mechanical stimuli and involves an increase in mineral density to manage increasing loads. Mechanical loading during childhood and adolescence enhances bone formation and strength, helping to prevent osteoporosis in later life, with similar effects seen in adulthood.[12]
Cardiovascular System
The cardiovascular system plays a crucial role in maintaining homeostasis during exercise by responding directly to the oxygen requirements of working muscles. To support the increased metabolic activity in skeletal muscle, the circulatory system regulates the transport of oxygen (O2) and carbon dioxide (CO2) and helps buffer the pH decrease in active tissues. Increasing cardiac output—the amount of blood pumped by the heart in 1 minute, calculated as heart rate × stroke volume—and modulating microvascular circulation achieve this adjustment in blood flow. As the workload rises, so does the cardiac output to meet the heightened metabolic demands. Additionally, local vasomediators, such as nitric oxide produced by endothelial cells, ensure sufficient local tissue blood flow as demand increases.
Aerobic exercise training leads to cardiovascular adaptations, including cardiac enlargement, enhanced myocardial contractility, and an increase in total blood volume. These adaptations enable greater ventricular filling and an increased stroke volume, measured in mL/beat. Furthermore, the increased capillary density improves the effective delivery of O2 to the tissues during exercise.[13]
Blood flow is preferentially shunted away from the gastrointestinal and renal systems and toward active muscles through selective constriction and dilation of capillary beds.[14] The increased skeletal muscle blood flow delivers O2 and aids in the removal of CO2. During exercise, the affinity of oxyhemoglobin for O2 decreases due to increased temperature, lower blood pH, and increased CO2 concentration. The reduced affinity enables red blood cells (RBCs) to extract CO2 and release O2 to the working muscles efficiently.[15][16]
The coronary arteries supply the myocardium with O2 and nutrients while removing metabolites. Increased cellular metabolism during exercise leads to increased coronary blood flow through vasodilation and capillary bed recruitment. This adaptation elevates O2 demand during exercise. The major determinants of myocardial O2 consumption (VO2) are heart rate, contractility, and myocardial wall stress, all of which markedly rise during exercise, thereby requiring a substantial increase in coronary blood flow.
The primary role of RBCs during exercise is to transport O2 from the lungs to the tissues and carry metabolically produced CO2 to the lungs for exhalation. On a mechanical level, senescent RBCs tend to be less compliant and are hemolyzed intraluminally when passing through capillaries in contracting muscles. This activity leads to an average decrease in RBC age since the younger RBCs have more favorable rheological properties. Younger RBCs also show increased O2 release compared to older RBCs. In addition, exercise increases erythropoietin levels, enhancing RBC production. These factors improve the body's O2 supply, gas exchange, and metabolic capacity over time during exercise.[17]
Plasma
Plasma volume expansion typically occurs after acute endurance exercise and endurance training. Hypervolemia may occur within minutes or hours after stopping exercise, with peak plasma volume expansion typically reached around 2 days after a marathon or similar long-distance race. This expanded volume can persist for up to 2 weeks after initiating such physical activity.
Fluid-regulating hormones, such as aldosterone, arginine vasopressin, atrial natriuretic factor, and increased plasma protein content contribute to hypervolemia. Greater plasma volume can enhance performance by improving muscle perfusion, increasing stroke volume, and maximizing cardiac output. Plasma volume expansion also improves the body's ability to regulate temperature during exercise by increasing skin blood flow. In most cases, an increase in plasma volume correlates with a lower hematocrit. True anemia results if plasma expansion is accompanied by red cell mass reduction. Relative anemia arises from plasma expansion without red cell mass lowering.[18]
Respiratory System
The respiratory system works in conjunction with the cardiovascular system to provide the tissues with O2. The respiratory system responds to exercise by immediately increasing pulmonary ventilation through the stimulation of the respiratory centers of the brainstem via the motor cortex and the muscle and joint proprioceptors during exercise.
The rise in CO2 production, hydrogen ions, and body temperature during exercise stimulates further increases in respiratory rate. In adults, pulmonary ventilation can increase from approximately 10 liters/minute at rest to more than 100 liters/minute at high-intensity efforts. The pulmonary circuit receives the same cardiac output as the systemic circuit. The available surface area for gas exchange increases in response to the increased cardiac output, resulting in a decrease in the alveolar dead space. Blood gas and pH balance can be maintained with more alveolar surface area available for gas exchange and increased alveolar ventilation due to increased frequency and volume of respiration. [19]
CO2 is one of the metabolic products of muscular activity and is carried away from peripheral active tissue, mostly as bicarbonate. A portion travels as dissolved CO2 in plasma and carbaminohemoglobin when bound to hemoglobin in RBCs. CO2 is readily incorporated into the RBC cytosol, where it is metabolized into carbonic acid by the enzyme carbonic anhydrase. Carbonic acid then spontaneously dissociates into a hydrogen ion and a bicarbonate ion. Once bicarbonate reaches the lungs, carbonic anhydrase catalyzes the reverse reaction to produce CO2, which is exhaled and removed from the body. The decreased alveolar dead space and increased tidal volume sustain the volume of carbon dioxide eliminated per unit of time in exercises of higher intensity.[20]
Endocrine System
Hormones modulate cellular growth. The key anabolic hormones whose function entails cellular growth and repair are discussed below.
Testosterone
Testosterone is an anabolic-androgenic steroid hormone that interacts with androgen receptors, stimulating skeletal muscle protein synthesis and, consequently, muscle hypertrophy. Testosterone levels increase, especially in response to resistance training.
Growth hormone
The pituitary gland releases growth hormone in response to acute and chronic exercise training. This hormone enhances bone and tissue growth.
Insulin-like growth factor
Insulin-like growth factors (IGFs) are small polypeptide hormones structurally related to insulin produced by the liver in response to growth hormone stimulation. Other tissues also produce IGFs in response to mechanical loading. IGFs play a vital role in the activation and proliferation of satellite cells, leading to an increase in myotube size, the number of nuclei per myotube, and damage repair. Additionally, these factors stimulate protein synthesis and muscle hypertrophy, axonal sprouting, and neuronal myelination.
Glucocorticoids
Glucocorticoids, mainly cortisol, in addition to the anabolic hormones, significantly impact human skeletal muscle. Cortisol increases during exercise. This hormone participates in glycemic regulation by stimulating gluconeogenesis, mainly in the hepatocytes, and inhibiting glucose uptake in myocytes and adipocytes. Cortisol also stimulates lipolysis in adipocytes, increasing the availability of metabolic substrates in skeletal muscle. This hormone also counteracts cellular inflammation and cytokine synthesis, thus aiding in maintaining vascular integrity and decreasing muscular damage.[21]
Cortisol levels follow a circadian rhythm, peaking in the morning, gradually decreasing throughout the day, and reaching their lowest levels around midnight. Systemic regulation occurs through the hypothalamic-pituitary-adrenal axis, while local control involves the action of 11β-hydroxysteroid dehydrogenase enzymes.[22]
Catecholamines
Plasma levels of epinephrine, norepinephrine, and dopamine increase during maximal exercise and return to baseline at rest, reflecting enhanced sympathetic nervous system activation. Catecholamines stimulate the sympathetic nervous system, raising the heart rate and cardiac output while promoting coronary artery vasodilation to enhance blood flow to the working myocardium and meet heightened O2 demands.[23]
Insulin
Insulin sensitivity refers to the amount of insulin needed to achieve 50% of its maximum effect on glucose transport. Reduced insulin sensitivity, or insulin resistance, impairs insulin action on glucose uptake, increasing the risk of developing type 2 diabetes. Improved insulin sensitivity means less insulin is required to achieve 50% of the maximum response.
Insulin sensitivity increases after long-term exercise. Moderate-intensity exercise of at least 30 minutes 3 to 5 days a week is linked to improved glycemic control. Muscle contraction during exercise activates adenosine monophosphate-activated protein kinase, increasing glucose uptake through the translocation of glucose transporter type 4 vesicles into working myocytes. This process is independent of insulin and only affects the muscle fibers undertaking the work during exercise, not the hepatocytes or adipocytes. This increased glucose uptake by the muscles can last for several hours after exercise. Insulin sensitivity increases after the immediate effect of exercise on glucose transport wears off.[24]
Skin
During exercise, the increase in blood flow facilitates skin thermoregulation to help sustain higher core temperatures. Exercise training produces microvascular adaptations that enhance the endothelium-dependent vasomotor functions of the skin. Endurance training shifts the threshold for vasodilation, resulting in increased skin blood flow at lower core temperatures. Thus, higher skin blood flow can be achieved with enhanced heat dissipation, thereby allowing longer and greater effort intensity.[25]
Immune System
The immune system responds to the extent and duration of exercise. The acute immune response to exercise depends on the intensity of the effort. Moderate exercise induces acute increases in interleukin 6 that exert direct anti-inflammatory effects. Exercise also causes a transient increase in white blood cells. Thus, engaging in daily exercise enhances immunity. However, heavy exercise can produce a transient immune dysfunction. For example, acute episodes of intense and prolonged exercise can lower salivary immunoglobulin A, decrease natural killer cell lytic activity, impair T- and B-cell function, and increase the risk of upper respiratory infections during the first 1 to 2 weeks following a race.[26]
For muscles to contract, the body must hydrolyze ATP to yield energy. These ATP-hydrolyzing pathways include substrate-level phosphorylation, which does not require oxygen, and oxidative phosphorylation, which relies on adequate oxygen delivery by the respiratory and cardiovascular systems to contract skeletal muscle. Additionally, oxidative phosphorylation depends on the supply of reducing agents derived from the breakdown of carbohydrates, fat, and, to a lesser extent, protein fuel stores. Exercise performance depends on substrate availability and use before, during, and after exercise.
"Substrate-level phosphorylation," or "anaerobic metabolism," refers to the use of the intramuscular stores of ATP during explosive exercise, as these molecules are small (~5 millimoles per kilogram wet muscle) and cannot sustain contractile activity for over a few seconds. Other metabolic pathways must be activated for more sustained exercise.
Oxidative phosphorylation or aerobic metabolism is typically used during sustained exercise, such as jogging or running. The oxidative phosphorylation pathway occurs in the inner mitochondrial membrane and produces substantially higher ATP quantities than other metabolic pathways. During low-intensity exercise, muscles use predominantly carbohydrates and fatty acids as substrates for energy production. Medium-chain fatty acids undergo β-oxidation in the mitochondrial matrix, while long-chain fatty acids need to be transported from the cytosol into the mitochondria with the help of carnitine.
The anaerobic energy pathways have a much higher rate of ATP production (representing power) but can generate a smaller amount of ATP (denoting capacity) than the aerobic pathways. During oxidative metabolism, fat oxidation yields a higher total ATP than carbohydrate oxidation. This factor contributes to the decrease in power output with carbohydrate depletion during prolonged, strenuous exercise.
Exercise capacity can be a useful measure of cardiovascular and pulmonary function, as well as a strong independent predictor of all-cause and disease-specific mortality. Impaired exercise tolerance can accompany coronary artery disease, peripheral vascular disease, cardiomyopathy, skeletal myopathies, and exercise-induced asthma. A thorough history often suggests any of these conditions, and a supervised exercise test can provide objective data.
To quantify exercise tolerance during history-taking, a healthcare provider may ask the number of flights of stairs a patient can tolerate or how many blocks they can walk without stopping. The time frame during which exercise tolerance changes may be happening must be noted.
VO2 measures oxygen consumption and is calculated as:
VO2 = Cardiac output x (Arterial O2 - Venous O2)
VO2 max measures aerobic exercise capacity at peak exercise, which is the highest O2 uptake rate an individual can maintain during intense activity. VO2 max, expressed as liters of O2 per minute, can be quantified by having a person exercise on a treadmill or bicycle at increasing intensity until exhaustion. During exercise, O2 uptake is calculated by measuring the volumes and concentrations of inspired and expired gas. The VO2 max improves with training and exercise, typically as a function of improved O2 delivery secondary to increased cardiac output and capillary density.
Healthy, motivated subjects can reach VO2 max during exercise testing. Patients with heart failure, muscular myopathies or dystrophies, and chronic obstructive pulmonary disease (COPD) may not be able to exert themselves to reach VO2 max. The 6-minute walk test may be used as a standardized measure in such cases. Exertional symptoms, such as effort limited by dyspnea, angina, palpitations, or claudication, imply the presence of a disease that requires further investigation.
Individuals with normal exercise capacity typically can provide a reasonable effort during exercise. These individuals reach a normal VO2 max and have dyspnea or fatigue as the reason for activity discontinuation. People with cardiopulmonary conditions, such as heart failure, COPD, and interstitial lung disease (ILD), are more likely to have an abnormal VO2 max and develop significant dyspnea, stopping exercise prematurely.
In people with pulmonary diseases, such as COPD and ILD, exercise intolerance often results from impaired gas exchange, which serves as the limiting factor. Exercise-induced bronchoconstriction, also known as exercise-induced asthma, is another pulmonary pathology to consider. This condition manifests as difficulty breathing and wheezing during or after exercise, with an objective indication being a decrease in forced expiratory volume in 1 second of 10% or more compared to baseline.
In heart failure or coronary artery disease, the increased demand for exercise on the heart can lead to myocardial strain. This issue becomes more pronounced in high-temperature or high-humidity exercise conditions. In response to impaired evaporative cooling, vasodilation occurs to reduce body temperature, resulting in a compensatory increase in heart rate. This elevated heart rate may further strain myocardial tissue due to ischemia or inadequate perfusion of the myocardium due to coronary artery compromise.
Exercise intolerance can also arise due to metabolically or structurally dysfunctional muscle tissue. Myopathies are suggested when significant cardiopulmonary issues are absent. Myopathies can present as muscle cramping or pain and are diagnosable with biopsy or genetic testing in some cases. Exercise intolerance may result from poor effort or excessive perception of limiting symptoms upon testing. In both cases, objective measures such as lactate levels help differentiate true exercise limitations from alternate explanations of intolerance.[27]
Over time, extended periods of inactivity cause skeletal muscles to atrophy and the body to become deconditioned. Therefore, patients who are hospitalized for extended periods must have an approved physical therapy consultation and program. Lastly, organ systems take time to adapt. If exercise intensity acutely increases past the body’s ability to repair itself, negative consequences, such as muscle strains, tears, and stress fractures, may result. Excessive training can also cause an adverse immune system response, while research shows that moderate-intensity exercise increases the immune response slightly.
In healthy adults older than 30, VO2 max decreases by about 10% per decade. This decline occurs secondary to cardiopulmonary limitations, such as increased myocardial fibrosis with loss of elastic recoil (reducing diastolic function), a decrease in maximal heart rate, increased chest wall rigidity, decreased alveolar surface area with capillary loss, and decreased respiratory muscle strength.
Maximal ventilation decreases by 6% per decade, and the pulmonary diffusion capacity diminishes by approximately 5% per decade. The most notable parameter of the aging process is the decrease in muscle mass and strength (sarcopenia), which occurs at a rate of 3% to 10% per decade, starting at age 25. However, the extent of these muscular changes depends on lifestyle, including regular exercise and nutrition. Therefore, improvement in VO2 max remains possible at older ages through consistent endurance training.[28]
Understanding basic exercise physiology is crucial, as impaired exercise tolerance in patients can allude to signs of underlying disease. Exercise testing can also help determine care goals and monitor prognosis and treatment progress in patients with cardiac, pulmonary, or cardiopulmonary disease.[29][30] A standardized exercise test can help determine the cause of exercise limitations. Understanding and applying exercise physiology can help reduce diagnosis time, improve outcomes, and ultimately improve patients’ quality of life.
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