Physiology, Skeletal Muscle Contraction

Cellular Level

Skeletal muscle is composed of cells collectively referred to as muscle fibers. Each muscle fiber is multinucleated with its nuclei located along the periphery of the fiber. Each muscle fiber further subdivides into myofibrils, which are the basic units of the muscle fiber. These myofibrils are surrounded by the muscle cell membrane (sarcolemma), which form deep invaginations called transverse tubules (T-tubules) within the myofibril. Each myofibril contains contractile proteins, described as thick and thin filaments, which are arranged longitudinally into units called sarcomeres.

The main unit of the thick filament is the large protein myosin, which is formed by two pairs of light chains, and one pair of heavy chains. The two heavy chains of myosin twist around each other to make the helical tail of the myosin, whereas the light chains interact with the heavy chains to form the two heads of the myosin at the other end. Upon the heads lies an important binding site which facilitates the interaction of myosin with actin, a protein belonging to the thin filament.[1]

The other contractile filament in myofibrils is the thin filament, mainly composed of three proteins: actin, tropomyosin, and troponin. Actin’s monomeric, globular form called G-actin, is polymerized into two strands that coil and intertwine around each other to give rise to filamentous actin, referred to as F-actin. Down the length of the F-actin are myosin-binding sites that are obscured by the filamentous protein tropomyosin. The function of tropomyosin is to prevent actin and myosin from interacting when the muscle is at rest, consequently preventing muscle contraction. Troponin is a three-protein complex located along the tropomyosin filaments. The first protein, Troponin T, facilitates the binding of troponin to tropomyosin. Troponin I serves the same purpose as tropomyosin in stopping the actin-myosin interaction by blocking the myosin-binding sites. Lastly, troponin C binds calcium to initiate muscle contraction.[2]

As mentioned previously, the thick and thin filaments of myofibrils are arranged in units called sarcomeres. The sarcomere is the fundamental contractile unit of the myofibril. Z lines separate each sarcomere. The A bands, located at the center of each sarcomere, contain the thick filaments, which may overlap with thin filaments. The A band further divides into the H zone, which contains no thin filaments. The prominent M line bisects the H zone and serves to connect the middle portions of the thick filaments. Located on both sides of the A band are the I bands, which contain both the thin filaments and the Z line that runs down the middle of each I band.

Mechanism

The nerves that are responsible for innervating muscle fibers are called motoneurons. A single motoneuron and the muscle fibers it innervates are collectively called a motor unit. The number of muscle fibers in a motor unit varies predictably with the function of the muscle. For example, the motor units responsible for the muscles of facial expression involve considerably fewer muscle fibers than the motor units responsible for the muscles involved in activities such as swimming. 

Skeletal muscle contraction begins first at the neuromuscular junction, which is the synapse between a motoneuron and a muscle fiber. Propagation of action potentials to the motoneuron and subsequent depolarization results in the opening of voltage-gated calcium (Ca2+) channels of the presynaptic membrane. Inward Ca2+ flow causes the release of acetylcholine (ACh) at the neuromuscular junction, which diffuses to the postsynaptic membrane at the muscle fiber. The postsynaptic membrane of the muscle fiber is also known as the motor endplate. ACh binds to the nicotinic receptors located at the motor endplate, depolarizing it, which initiates the action potentials in the muscle fiber.

Excitation-contraction coupling refers to the mechanism that converts the action potentials mentioned above in the muscle fibers into muscle fiber contraction. The action potentials at the muscle cell membrane surrounding the myofibrils travel into the T-tubules, which are responsible for propagating the action potential from the surface to the interior of the muscle fiber. T-tubules contain dihydropyridine receptors that are adjacent to the terminal cisternae of the sarcoplasmic reticulum of the muscle fiber. When T-tubules become depolarized, their dihydropyridine receptors undergo a conformational change that mechanically interacts with the ryanodine receptors on the sarcoplasmic reticulum. This interaction opens the ryanodine receptors causing Ca2+ to release from the sarcoplasmic reticulum. The resulting increased intracellular Ca2+ attaches to troponin C of the troponin complex on the thin filaments. The interaction between Ca2+ and troponin C exhibits cooperativity, which means that each Ca2+ that binds troponin C increases the affinity of troponin C binding for the next Ca2+ molecule, up to a total of four Ca2+ ions per troponin C. As a result of Ca2+ binding, the troponin complex undergoes a conformational change causing displacement of tropomyosin from the myosin-binding sites on F-actin, which allows myosin of the thick filaments to bind.[2][3]

The cross-bridge cycle, an event that occurs during excitation-contraction coupling, refers to the mechanism by which the thick and thin filaments slide past one another to generate a muscle contraction. At the beginning of the cycle, when myosin is tightly bound to actin, no adenosine triphosphate (ATP) is bound to myosin, a state known as rigor; this is a transient state in contracting muscle, whereas, in the absence of ATP, such as in death, this state is permanent and is called rigor mortis. Next, ATP binds to the myosin head, inducing a conformational change in myosin that decreases its affinity for actin. Consequently, myosin dissociates from actin and the myosin head becomes cocked toward the end of the sarcomere. The ATP bound to myosin becomes hydrolyzed to adenosine diphosphate (ADP) and one inorganic phosphate molecule, which both remain linked to myosin. In its cocked position, myosin then binds to a new site on the actin, creating a power stroke that pulls the actin filaments. Each cross-bridge cycling event results in the myosin head progressing up the actin filament under the condition that Ca2+ remains bound to troponin C. Finally, ADP is released, and myosin returns to its original state of rigor where it is bound to actin in the absence of ATP.[4]

After contraction, muscle relaxation occurs when Ca2+ reaccumulates in the sarcoplasmic reticulum via the active Ca2+ ATPase (SERCA) pump on the sarcoplasmic reticulum membrane. This pump transports the intracellular Ca2+ into the sarcoplasmic reticulum, which maintains low intracellular Ca2+ when the muscle is relaxed. Within the sarcoplasmic reticulum is a Ca2+ binding protein called calsequestrin, which serves to decrease free Ca2+ concentration to reduce the amount of work required by the SERCA pump. When intracellular Ca2+ concentration decreases, Ca2+ dissociates from troponin C, allowing tropomyosin to resume blocking the myosin-binding sites on F-actin.[5]

The events of excitation-contraction coupling are always sequential and exhibit a temporal relationship. In other words, the muscle fiber action potential always precedes the increase in intracellular Ca2+, which always precedes muscle contraction. One single action potential leading to an increased intracellular Ca2+ from sarcoplasmic reticulum release produces a single muscle contraction known as a twitch. Because the action potential duration is shorter than the twitch duration, the muscle fiber may be activated again before muscle relaxation occurs. If an already active muscle fiber becomes stimulated again, there is insufficient time for the sarcoplasmic reticulum to reaccumulate Ca2+. Consequently, intracellular Ca2+ remains high, and the force of the second stimulus becomes an additive effect to the remainder of the first stimulus, resulting in additional force. This phenomenon of sustained contraction is called tetany.

The length-tension relationship in muscle illustrates the tensions, or forces, produced from the cross-bridge cycle as a result of changes in muscle fiber length. The tension is determined by altering the resting length of a muscle that has already undergone isometric contraction. This resting length, also known as preload, therefore, is from passive precontraction from isometric contraction. Passive tension refers to the tension that results simply from increasing the muscle length. As preload increases and the muscle is made longer, its tension further increases. Passive tension can be thought of as the tension produced in an elastic rubber band as it stretches further. Active tension is the tension developed from the cross-bridge cycle and is proportional to the actual number of cross-bridges. This tension is highest when there is an optimum overlap between myosin and actin, resulting in a maximal number of cross-bridges. When muscle length decreases, crowding of the filaments occurs, which reduces tension. Similarly, when muscle length increases, active tension becomes diminished because there is less overlap between myosin and actin, and by extension, fewer cross-bridges. The total tension is the tension resulting from muscle contracting at different preloads and is equal to the sum of active tension and passive tension.[6]

The force-velocity relationship refers to the velocity of muscle shortening as a function of afterload, which is the force against which the muscle contracts. In this relationship, the afterload is a fixed variable, in contrast to the length-tension relationship, when the muscle length was the fixed variable. As afterload increases, shortening velocity decreases. Maximal velocity occurs when there is zero afterload on the muscle.[7]

Concentric contraction refers to when the force of contraction exceeds the force of resistance, which results in muscle shortening and approximation of muscle origin and insertion. Eccentric contraction occurs when the force of contraction is less than the force of resistance. In other words, the force of resistance is greater than that of contraction, resulting in muscle lengthening and an increased distance between muscle origin and insertion.

Pathophysiology

Malignant hyperthermia is a life-threatening condition that occurs primarily in individuals with a genetic predisposition with a mutation in the ryanodine receptor of the sarcoplasmic reticulum. When these individuals suffer exposure to volatile anesthetic agents or the muscle relaxant succinylcholine, there is a massive release of intracellular Ca2+ from the ryanodine receptors and insufficient Ca2+ sequestration by the SERCA pump. This mechanism results in muscle contraction, rhabdomyolysis, severe hyperthermia, and possibly death. The only treatment for malignant hyperthermia is dantrolene, which binds to the ryanodine receptor to prevent further Ca2+ release.[8]

Myasthenia gravis is an autoimmune disease that affects the neuromuscular junction. It is characterized by fatigable skeletal muscle weakness that worsens with repetitive movements and improves with rest. Most commonly, myasthenia gravis initially involves weakness of the ocular muscles with eventual progression to limb muscles. Most patients with this disease have autoantibodies against the nicotinic ACh receptors of the neuromuscular junction, which causes endocytosis and degradation of the receptors. Without ACh binding to the receptors, action potentials are unable to propagate down the muscle fiber, and consequently, muscle weakness occurs. Acetylcholinesterase inhibitors prevent the breakdown of ACh and are used to increase neuromuscular transmission as a treatment for myasthenia gravis.[9]

Botulinum toxin is an agent that alters neuromuscular function. This toxin, produced by C. botulinum, prevents the release of ACh from the presynaptic membrane of the motoneuron. Consequently, skeletal muscle is unable to contract, resulting in flaccid paralysis.[10]

Skeletal muscle cramps are due to sudden and involuntary muscle contractions that last from seconds to minutes resulting in pain. Although they may be associated with diseases, muscle cramps most commonly occur in the absence of any clear pathology. They most frequently present in patients who are elderly, pregnant, or exercising vigorously. Because cramps are the product of muscle contractions, immediate relief from the pain may be provided from stretching the muscle affected.[11]

Clinical Significance

The evaluation of muscle strength and muscle contraction is a routinely included procedure in the patient physical exam. The Medical Research Council Manual Muscle Testing scale is the most commonly used muscle strength grading system, where scores from 0 to 5 are assigned based on patient ability. A score of 0 refers to no muscle activation. Scoring of 1 means that there is only slight contractility of the muscle. A score of 2 is when there is muscle activation tested in the absence of gravity. 3 refers to muscle activation against gravity but not with resistance. 4 is muscle activation against gravity, and some resistance and 5 is muscle activation against both gravity and full resistance. The primary purpose of muscle strength testing in the physical exam is to evaluate and determine a differential diagnosis for when a patient presents with complaints of weakness, often in the setting of neurologic disease.[12]