Introduction

Exercise substantially increases the body's demand compared to its resting state. At rest, the nervous system maintains a parasympathetic tone, which affects respiratory rate, cardiac output, and various metabolic processes. Exercise stimulates the sympathetic nervous system and induces an integrated response from the body. This response maintains an appropriate level of homeostasis for the increased demand in physical, metabolic, respiratory, and cardiovascular efforts.

Issues of Concern

Cardiovascular disease remains 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. Lack of exercise tends to exacerbate the deleterious effects of these risk factors, while implementing exercise in daily routine has been shown to reduce mortality rates. Specifically, the lack of exercise is directly linked to obesity while also playing a role in the development of diabetes and hypertension.[1][2][3]

Research shows that exercise, in conjunction with other lifestyle modifications, can reduce the risk of hypertension regardless of inherent genetic predispositions; also, exercise has been shown to increase insulin sensitivity in the management approach to diabetes.[4][5][6]

• Healthy body weight can be attained through lifestyle modifications to reduce cardiovascular disease mortality.
• Exercise is a noninvasive and nonpharmaceutical intervention, so it has a pivotal role in making it accessible and improving quality of life.

Cellular Level

Working from gross anatomy to cellular anatomy, we start at the skeletal muscle level. Within each skeletal muscle, hundreds of muscle fibers are compartmentalized in an organized fashion linearly. They work in tandem to shorten muscle upon contraction.

The outermost layer of the muscle is the epimysium. Within this layer, muscle fibers are bundled into muscle fascicles. Deeper than this is the perimysial layer, which encompasses the endomysial layer, which ultimately holds the individual muscle fibers (aka myocytes).

There is the sarcolemma (plasma membrane of the muscle fiber) at the muscle fiber level. The sarcoplasm is analogous to the cytoplasm, and the sarcoplasmic reticulum is akin to a smooth endoplasmic reticulum. Finally, we have myofibrils composed of contractile actin and myosin filaments.

Within all of this, the functional unit of a myofibril is the sarcomere. It is comprised of an organization of contractile myofilaments. These myofilaments are the actin filaments (thin filaments) and the myosin filaments (thick filaments). One sarcomere is defined as the filaments between 2 Z-disks. The center of the sarcomere is the M-line, which anchors the thick myosin filaments. The I-band is the area adjacent to the Z-lines where myosin filaments do not overlap actin filaments. Sarcomeres are arranged end-to-end along the entire muscle fiber length, and each unit's synchronized contraction produces a visible muscle contraction.

Organ Systems Involved

Physical activity induces a coordinated response of multiple organ systems.[7][8][9][10]

Musculoskeletal System

The musculoskeletal system is at the forefront. Three types of muscle fibers have different characteristics. Higher myosin ATPase activity is directly proportional to faster muscle contraction speed, while higher oxidative capacity relates to fatigue.

Type-I fibers are known as slow-twitch fibers. These fibers have abundant mitochondria and myoglobin with great vascular supply. 

• They have low myosin ATPase activity, high oxidative, and low glycolytic capacity.
• They are resistant to fatigue.
• These fibers are predominant in postural muscles as they provide low force but don’t fatigue as easily as the others.

Type-IIa fibers are known as fast-twitch oxidative fibers.

• They have high myosin ATPase activity and oxidative and glycolytic capacity.
• They are relatively resistant to fatigue.
• These fibers are recruited for power activities requiring sustained effort, such as lifting weights for multiple repetitions.

Type-IIa fibers are the middle ground between the slow but fatigue-resistant type-I fibers and the fast but fatigue-prone type-IIb fibers.

Type IIb fibers are known as fast-twitch glycolytic fibers.

• They have high myosin ATPase activity, low oxidative, and high glycolytic activity.
• They rapidly fatigue.
• These fibers are recruited for high-intensity, short-duration exercises such as full-effort sprints.

With the introduction of progressively overloading exercise training, we can expect skeletal muscle fibers to hypertrophy, increasing in diameter and volume. Muscle contraction acts upon the skeleton and initiates movement. When a progressive force is applied to the muscles over time, they adapt to the increasing load.

Satellite cells play a role in this repair and growth process. Exercise, whether through long-distance running or powerlifting, places a burden of stress on muscle fibers and bones, which causes micro-tears and trauma. Satellite cells are activated and mobilized to regenerate damaged muscle tissue. This process is made possible by donating daughter nuclei from the satellite cells after multiplication and fusion. Bones increase their mineral density over time to manage this increasing load.

Circulatory System

The circulatory system plays a critical role in maintaining homeostasis during exercise. To accommodate the increased metabolic activity in skeletal muscle, the circulatory system must properly control the transport of oxygen and carbon dioxide and help buffer the pH level of active tissues. This action is accomplished by increasing cardiac output (heart rate and stroke volume) and modulating microvascular circulation. Also, the action of local vaso-mediators, such as nitric oxide from endothelial cells, helps to ensure adequate blood flow.

Blood flow is preferentially shunted away from the gastrointestinal (GI) and renal systems and toward active muscles through selective constriction and dilation of capillary beds. This increased skeletal muscle blood flow provides oxygen while facilitating carbon dioxide removal. The increased metabolic activity increases carbon dioxide concentrations and shifts the pH to the left, which further facilitates erythrocytes (RBC) to extract carbon dioxide (CO₂) and release oxygen (O₂). On a mechanical level, RBCs that have been in circulation for a long time tend to be less compliant than younger RBCs, meaning that during exercise, older RBCs can be hemolyzed intravascularly when passing through capillaries in contracted muscles. This activity leads to an average decrease in RBC age since the younger RBCs have more favorable rheological properties. Younger RBCs also have increased oxygen release compared to older RBCs. Exercise increases erythropoietin (EPO) levels, which causes an increase in RBC production. Both of these factors improve the oxygen supply during exercise. Over time, muscle vascularization also improves, improving gas exchange and metabolic capacity over time.

Respiratory System

The respiratory system works in junction with the cardiovascular system. The pulmonary circuit receives almost all of the cardiac output. In response to the increased cardiac output, perfusion increases in the apex of each lung, increasing the available surface area for gas exchange (decreased alveolar dead space).

With more alveolar surface area available for gas exchange and increased alveolar ventilation due to increased frequency and volume of respiration, blood gas and pH balance can be maintained. Going into more detail, CO₂ is 1 of the metabolic products of muscular activity. CO₂ is carried away from peripheral active tissues in various forms. Most are transported in bicarbonate, but a portion travels as dissolved CO₂ in plasma and as carbaminohemoglobin on RBCs. CO₂ readily dissolves into the cytosol of erythrocytes, where it is acted upon by carbonic anhydrase to form carbonic acid. Carbonic acid then spontaneously dissociates into a hydrogen ion and bicarbonate. After being transported to the lungs, a high oxygen environment (Haldane effect), this reaction is catalyzed in the opposite direction to reverse itself and produce CO₂, which is exhaled and removed from the body. As mentioned before, the decreased alveolar dead space and increased tidal volume sustain the volume of carbon dioxide (VCO₂) eliminated per unit of time in exercise of higher intensity.

Endocrine System

• Plasma cortisol, epinephrine, norepinephrine, and dopamine levels increase with maximal exercise and return to baseline after rest. This increase is consistent with the body's increase in sympathetic nervous system activation.
• The pituitary gland releases growth hormones to enhance bone and tissue growth.
• Insulin sensitivity increases after long-term exercise.
• Testosterone levels also increase, enhancing growth, libido, and mood.

Function

Exercise has demonstrated many health benefits.[11][12] Through functional exercise, we can see benefits in but not limited to:

• Cognition: Studies have shown exercising subjects to have higher concentration scores than non-exercising subjects.
• Flexibility and mobility 
• Cardiovascular health
• Improved glycemic control and insulin sensitivity
• Mood elevation
• Lower risks of cancer
• Increased bone mineral density 

Through a properly executed exercise program, the body adapts and becomes more efficient at performing various exercises. Some of these adaptations are:

Musculoskeletal system

• Increased muscle capillary perfusion
• Increased strength due to muscle hypertrophy
• Increased endurance due to increased muscular mitochondrial content
• Increased bone density

Cardiovascular

• Improved contractility
• Increased blood vessel diameter
• Increased capillary density
• Improved vasodilation
• Decreased average blood pressure at rest or submaximal activity due to the increased efficiency

Mechanism

For muscles to contract, the body must hydrolyze adenosine triphosphate (ATP) to yield energy. The ways muscles maintain ATP levels are contingent upon the conditions of the body. Muscles can utilize glucose or glycogen in both aerobic and anaerobic manners. The glycolytic energy system tends to lead to lactate accumulation and subsequent pH decrease in muscle tissue, especially in the anaerobic setting.

Aerobic metabolism is typically utilized in exercises such as walking, while anaerobic metabolism participates in high-intensity activities such as weightlifting. The oxidative phosphorylation pathway is the major source of ATP for cells; this is part of the aerobic pathway that occurs on the inner mitochondrial membrane and produces much more ATP than other metabolic pathways. 

• Complex I: Receives electrons from NADH.
• Complex II: Receives electrons from succinate; the electrons from NADH and succinate are transferred by coenzyme Q10 to complex III
• Complex III: The electrons from here are transferred by cytochrome C to complex IV
• Complex IV: Electrons at this subunit are accepted by oxygen, which yields water. 
• Complex V: ATP is created when the protons return to the electron gradient. 

During high-intensity exercises such as HIIT (high-intensity interval training) or intense weight training, muscles cycle through ATP rather quickly, resulting in a pool of ADP. Phosphocreatine can donate a phosphate group to ADP to regenerate additional ATP, which affords muscle energy. Creatine kinase catalyzes this reaction. 

During rest and low-intensity exercise, muscles can utilize fatty acids as substrates for energy production. Medium-chain fatty acids undergo beta-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.

When a motor unit receives an excitation signal, the axon terminal releases acetylcholine, a neurotransmitter, onto receptors of the sarcolemma. This signal opens voltage-gated channels and creates an action potential that passes along the T-tubules to conduct a coordinated signal deep into the muscle. When that depolarization reaches the sarcoplasmic reticulum, it causes a release of its stored calcium ions. 

When these calcium ions are released, they bind to troponin C in the sarcoplasm, which initiates unblocking of the actin-binding site on myosin due to tropomyosin. Essentially, calcium binds to troponin, which causes tropomyosin to unbind from the actin-myosin binding site, exposing the site, which now allows the binding of actin and myosin together, which creates a contractile force and shortening of the sarcomere unit. ATP is hydrolyzed to ADP and phosphate when the myosin head causes this contraction. To relax from the contracted state, ATP must bind to myosin, which causes a release of the actin site and the return to the high-energy state of myosin. This shortening and lengthening model is explainable by the sliding filament theory in which actin and myosin filaments slide past each other to shorten the length of the sarcomere. There are a few different types of muscle contractions.

Isometric contraction: The muscle is actively contracting, but its length does not change due to equal and opposite forces in opposite directions.

• Holding a plank position or carrying groceries with the arm halfway flexed and held in position.

Concentric contraction: The muscle is actively contracting and decreasing its length due to greater muscle force relative to its opposing force, which approximates its attachment and origin.

• Dumbbell bicep curl, bench press, squats

Eccentric contraction: The muscle is actively contracting yet increasing its length; the muscle contracts with less force than its opposing force. 

• The “negative” portion of the exercise mentioned above
• The lowering portion of the bicep curl (from arm flexion->arm extension), the lowering portion of the bench press (from arm extension and pectoral flexion to arm flexion and pectoral extension), and the lowering portion of a squat from standing to a squat position

Related Testing

Exercise capacity can be a useful measure of cardiovascular and pulmonary function. Impaired exercise tolerance can reflect dysfunction in any 1 of the involved organ systems. Symptom onset during a controlled exercise test can suggest conditions such as angina, peripheral vascular disease, or exercise-induced asthma. Often, a thorough history taken from the patient can also recommend these conditions, but a supervised exercise test can be much more objective.

In the inquiry, to quantify exercise tolerance, a healthcare provider may ask the number of flights of stairs a patient can tolerate or how many blocks they can walk without stopping. It’s important to note the time frame upon which exercise tolerance changes may be happening. Acute versus chronic capacity changes can suggest different etiologies of disease.

VO₂ is the consumption of oxygen and is explainable by the Fick equation. This equation states that VO₂ = [Cardiac Output] x [Difference in arterial and venous oxygen levels]. VO₂ max measures aerobic exercise capacity, the highest oxygen uptake rate an individual can maintain during intense activity. VO₂ max (in L of oxygen per minute) can be measured by having a subject perform an exercise on a treadmill or bicycle with increasing intensity. During the exercise, oxygen uptake is calculated by measuring the volumes and concentrations of inspired and expired gas. As patients exercise and train, their VO₂ max may improve, but this is typically a function of oxygen delivery, not skeletal muscle oxygen extraction. Through training, oxygen delivery improves due to the increased cardiac output and capillary density.

Asymptomatic patients who are motivated can reproduce their VO2max during testing. Symptomatic patients who have congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) may not be able to exert themselves to reach VO₂ max fully. We can utilize the 6-minute walk test 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 must require investigation.

Pathophysiology

In patients who provide reasonable effort during the test and reach a normal VO₂ peak (good effort without reaching VO₂ max) and who state dyspnea or fatigue was their limiting factor during exercise, we can assume that they have a normal exercise tolerance. In this case, we can assume that a cardiopulmonary issue such as CHF, interstitial lung disease (ILD), or COPD was absent. We would be more likely to see an abnormal VO₂ peak with significant dyspnea when testing these patients.

In pulmonary diseases such as COPD and ILD, exercise intolerance may be due to an impairment in gas exchange being the limiting factor. Exercise-induced bronchoconstriction (exercise-induced asthma) is another pulmonary pathology to consider. It presents as difficulty breathing and wheezing during or after exercise. Objectively, it can be indicated by FEV1 decrease greater than 10% compared to baseline.

Exercise can be particularly dangerous in cardiac diseases, such as valvular abnormality, CHF, or CAD. The increased demand on the heart can lead to myocardial strain. This issue becomes intensified in high-temperature or high-humidity exercise conditions. In response to the impaired evaporative cooling, vasodilation occurs to reduce body temperature, which leads to a compensatory increase in heart rate, which causes additional strain on the myocardial tissue.

Exercise intolerance can also arise due to metabolically/structurally dysfunctional muscle tissue. Myopathies are suggested when any 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.

Over time, extended periods of inactivity cause skeletal muscles to atrophy and the body to become deconditioned. Therefore, it is recommended that patients who are hospitalized for extended periods have an approved physical therapy consultation and program. Lastly, it is essential to note that 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.

Clinical Significance

Understanding basic exercise physiology is crucial as impaired exercise tolerance in patients can allude to signs of underlying disease when combined with modalities such as ECGs. Exercise testing can also help determine care goals and monitor prognosis and treatment progress.[13][14] Through a standardized exercise test, one can determine the broad etiology of the exercise limitation and then pursue testing to narrow the differential to a specific cause. Understanding and applying exercise physiology can help reduce diagnosis time, improve outcomes, and ultimately improve patients’ quality of life.