• Introduction
  • The basic mechanisms of muscle contraction
  • The sliding filament theory of muscle contraction
  • Regulatory proteins
  • ATP and muscle contraction
  • Excitation-contraction coupling
  • Control of muscle tension
  • Final thoughts
  • Sources
  • A band: anisotropic bands - dark bands that corresponds to the thick (myosin) filaments.
  • Actin: an abundant intracellular protein found in all eukaryotic cells. These thin filaments play a crucial role in muscle contraction and in cell movements.
  • H zone: an area in the middle of the A zone, where only thick filaments are present. Has a somewhat lighter appearance than the overlap region of the A band.
  • I band: isotropic bands - light bands that contain only thin filaments (actin). Located between two thick filaments.
  • M line: the attachment site for the thick filaments located in the center of the A band, and therefore also at the center of the sarcomere.
  • Myoblast: the embryonic precursors of myocytes (muscle cells)
  • Myofibril: a basic rod-like organelle of a muscle cell made up of repeating subunits called sarcomeres. Myofibrils constitute the contractile system, which consists of four complex proteins: myosin, actin, tropomyosin, and troponin.
  • Myosin: a type of molecular motor and converts energy from the hydrolysis of ATP into mechanical energy.
  • Neuromuscular junction: a synaptic connection between the terminal end of a motor nerve and a muscle.
  • Power stroke: the force generating step used by myosin motor proteins.
  • Sarcomere: the smallest contractile unit of a muscle fiber.
  • Sarcoplasmic reticulum: a specialized form of the endoplasmic reticulum of muscle cells that is important in transmitting the electrical impulse and in the storage of calcium ions, into the sarcoplasm.
  • T-tubules: invaginations of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells.
  • Tropomyosin: a family of actin-binding proteins that are important in both muscle and nonmuscle cells.
  • Troponin/troponin complex: a complex of three regulatory proteins (troponin C, troponin I, troponin T) that are needed for muscle contraction.
  • Z-disc/Z line: the boundaries of a single sarcomere where thin (actin) filaments attach. 

Introduction

Muscle cells are highly specialized for a single task, contraction. There are three types of muscle tissue in vertebrates: skeletal muscle, which is responsible for voluntary movements; cardiac muscle, which pumps blood from the heart; and smooth muscle, which is responsible for involuntary movements of organs (e.g. bronchi, intestines, stomach, uterus, blood vessels, etc.). Skeletal and cardiac muscle are types of striated muscle tissue, whereas smooth muscle tissue is non-striated.

Skeletal muscles consist of bundles of muscle fibers – large multinucleated cells (~50 μm in diameter and up to several centimeters in length) formed by the fusion of individual myoblasts (embryonic precursors of muscle cells) during development. Muscle fibers contain numerous tubular myofibrils, which are composed of repeating sections of sarcomeres – the basic contractile units of muscle fibers. Sarcomeres are composed of long, fibrous protein filaments called actin (thin filament, approximately 7 nm in diameter) and myosin (thick filament, approximately 15 nm in diameter). Under electron microscopy, these filaments form several distinct lines, as well as light and dark areas, known as bands. Each of which describes a specific area of the sarcomere.

  • A band: anisotropic bands – dark bands that corresponds to the thick (myosin) filaments.
  • H zone: an area in the middle of the A zone, where only thick filaments are present. Has a somewhat lighter appearance than the overlap region of the A band.
  • I band: isotropic bands – light bands that contain only thin filaments (actin). Located between two thick filaments.
  • M line: the attachment site for the thick filaments located in the center of the A band, and therefore also at the center of the sarcomere.
  • Z disc/Z line: the boundaries of a single sarcomere where thin (actin) filaments attach.

Muscle contraction occurs when actin and myosin filaments slide past each other, resulting in the shortening of the sarcomere. This phenomenon, known as the sliding filament theory, forms the basis of how muscles contract and relax. This post explains the basic mechanisms behind muscle contractions, including the sliding filament theory, how muscles use adenosine triphosphate (ATP), and the role of regulatory proteins during the shortening of the muscle.

The basic mechanisms of muscle contraction

The process of muscle contraction begins with a signal from the soma, the body of the alpha motor neuron located in the spinal cord. This neuron can be either stimulated or inhibited through the information provided by sensory and reflex neurons as well as the central nervous system. If the stimulus is strong enough to create an electric signal (depolarization) in the soma, the signal (action potential) propagates down the axon (nerve fiber) of the efferent motor neuron towards the neuromuscular junction (a synaptic connection between the terminal end of a motor nerve and a muscle). This process of converting the action potential from the motor neuron to the muscle fiber is known as neuromuscular transmission. 

The sequence of events that result in the contraction of a single muscle fiber starts when the action potential arrives at the neuromuscular junction. This signal causes the nerve ending to release acetylcholine (ACh), a neurotransmitter, which subsequently travels across the junction to the sarcolemma (a specialized cell membrane which surrounds striated muscle fiber cells). When acetylcholine reaches the sarcolemma, it attaches to acetylcholine receptors which opens sodium ion channels. As positively charged sodium ions (Na+) enter the sarcolemma, the membrane depolarizes. This action potential quickly spreads to the rest of the membrane, including the T-tubules (extensions of the cell membrane that penetrate into the center of skeletal muscle cells, allowing for rapid transmission of action potential into the cell). This triggers the release of calcium ions (Ca2+) from the sarcoplasmic reticulum, a specialized form of the endoplasmic reticulum of muscle cells that is important in transmitting the electrical impulse and in the storage of calcium ions, into the sarcoplasm (the cytoplasm of striated muscle cells). Then, the released Ca2+ bind to troponin, which removes tropomyosin from the myosin-binding site, allowing myosin to attach with actin to form cross-bridges (the attachment of myosin with actin within the muscle cell) as long as ATP is available to drive cross-bridge cycling. Thus, allowing myosin heads to pull the actin inwards and shorten the muscle to its anatomical limit. This entire process that links plasma membrane stimulation with cross-bridge force production is known as excitation–contraction coupling, and it forms the basis of muscle contraction at a cellular level. 

The muscle relaxes as soon as the impulse (signal) from the motor neuron ends. This stops the release of Ca2+, which repolarizes the sarcolemma and T-tubules, as well as closes the calcium channels in the sarcoplasmic reticulum. Ca2+ are then actively pumped back into storage within the sarcoplasmic reticulum, causing troponin and tropomyosin to cover the active binding sites on the actin strands. As a result, the cross bridges of the myosin filament have no way of attaching to the actin in order to pull it inwards.

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Muscle Contraction

The sarcomere is the smallest functional unit of a muscle fiberSarcomeres consist of thin actin and thick myosin filamentsThe sarcomere shortens as the filaments slide past each otherMuscle contraction is a multi-step process:1) Depolarization and calcium ion release following an action potential2) Actin and myosin cross-bridge formation3) Sliding mechanism of actin and myosin filament4) Sarcomere shortening (muscle contraction)

The sliding filament theory of muscle contraction

The sliding filament theory is based on the findings of A.F. Huxley and R. Niedergerke (1954) and H.E. Huxley and J. Hanson (1954) who studied the molecular basis of muscle contraction. Their findings resulted in two groundbreaking scientific papers; one describing the position of myosin (thick) and actin (thin) filaments at various stages of muscle contraction, and the second proposing how actin and myosin interact to produce contractile force. These findings paved the way to our current understanding of how muscles contract.

When observed under a microscope, the Z discs/Z lines (the peripheries of a sarcomere) move closer together during muscle contraction. As a result, the width of the H zone (the center of the A band with no overlap between the thick and the thin filaments) decreases, giving it a darker appearance. The A band, which contains thick filaments of myosin, remains at a constant length while other regions of the sarcomere shorten. However, the I bands (the segment between two neighboring Z-discs) are comprised of thin actin filaments, and change their length with the sarcomere. This led to the conclusion that actin and myosin must slide past one another to shorten the sarcomere and generate muscle tension. In short, muscle contraction occurs due to the sliding of the thin filaments (actin) over the thick filaments (myosin) within the muscle fiber. 

In order for myosin heads to pull actin inwards, it must form cross-bridges (the attachment of myosin with actin within the muscle cell) with the thin filament. This requires a complex interplay between actin and myosin filaments, adenosine triphosphate (ATP) and two regulatory proteins; troponin and tropomyosin. The continuous formation and breaking of cross bridges (cross-bridge cycling) continues until the sarcomere has contracted to its anatomical limit or ATP is no longer available. 

Regulatory proteins

Tropomyosin is a protein that winds around the actin filaments and covers the myosin-binding sites. This prevents cross-bridge formation, which in turn, prevents the muscle from contracting without nervous input. Together with troponin (a protein subunit with a binding site for Ca2+), tropomyosin forms a troponin-tropomyosin complex – a protein complex to which calcium binds to in order to trigger muscle contraction. 

In a relaxed muscle, actin and myosin are separated. Upon activation by an action potential, the calcium channels in the sarcoplasmic membrane are opened and calcium is released into the sarcoplasm. The released Ca2+ then binds to the troponin molecule, triggering conformational changes in the arrangement of troponin and tropomyosin, which allows tropomyosin to move away from the myosin-binding sites on actin. Once these binding sites are exposed, the myosin heads are able to bind to these sites and form cross-bridges. The myosin heads then pull the thin filaments towards the center of the sarcomere. However, each head can only pull actin a short distance before it must be ”re-cocked”. This step also requires ATP to function.

The aforementioned cross-bridge cycle of the contraction process continues until tropomyosin covers the binding sites on actin, or Ca2+ and ATP are no longer available.

ATP and muscle contraction

Muscles contract and relax in a repetitive cycle of binding and releasing of actin and myosin filaments. During contraction, myosin heads bind to actin and pull the actin inwards. This action also requires energy, which is provided by adenosine triphosphate (ATP). In the beginning of the cross-bridge cycle, a part of the myosin head is attached to the binding site on the actin. However, myosin also has a binding site for ATP. As the ATP binds with myosin, it causes the myosin head to detach from the actin. After this occurs, ATP is hydrolyzed (a chemical reaction that uses water to break down a compound) into adenosine diphosphate (ADP) and inorganic phosphate (Pi ) by the enzyme ATPase. The energy released in this process changes the angle of the myosin head into a ”cocked” position. The myosin is now in a high-energy state and ready to bind to actin if binding sites are available, but both ATP and Pi remain attached.

Once myosin forms a cross-bridge with actin, the phosphate generated in the previous contraction dissociates (is released), resulting in a stronger bond between myosin and actin. This subsequently triggers a power stroke (the force generating step used by myosin motor proteins), where the myosin head moves toward the M-line at the center of the sarcomere, pulling the actin along with it. As the myosin head returns back to its original position, the filaments move ~10 nm toward the M-line. Thus, causing the sarcomere to shorten. After the power stroke, ADP is released but the previously formed actin-myosin cross-bridge remains intact. The myosin head is now in a low-energy state.

The released phosphate then rebinds to ADP, converting it to ATP. This newly formed ATP binds to myosin and breaks the cross-bridge between actin and myosin filaments. Thus, freeing the myosin for the next contraction. As long as ATP is available, it binds to myosin and maintains cross-bridge cycling, allowing the muscle to continue to contract. In the absence of ATP, the myosin head will not detach from actin, and the muscles would remain in a contracted state, rather than a relaxed state.

Note that each thick filament of approximately 300 myosin molecules has several myosin heads – all of which continuously form and break cross-bridges during muscle contraction. Additionally, when considering how many sarcomeres are in a myofibril, let alone in a muscle fiber, or an entire muscle, it is easy to see why ATP is so crucial for voluntary muscle movements.

Excitation-contraction coupling

Excitation-contraction coupling refers to the link between the action potential and the start of a muscle contraction. This process starts when an action potential reaches the neuromuscular junction – a site where neuronal axon terminals (synaptic terminals) come into contact with the motor end plate (a chemical synapse formed where the terminal branches of the axon come into contact with a muscle cell) of the muscle fiber. These two membranes are separated by a small space known as the synaptic cleft. In order to move across the synaptic cleft, the electrical signal must be turned into a chemical signal. This is done via acetylcholine (ACh) – a neurotransmitter that diffuses across the synaptic cleft and binds onto receptors on the motor end plate. 

The motor end plate has several junctional folds that provide a larger surface area for the neurotransmitters to bind to receptors. These receptors are sodium channels that open up following a neurotransmitter signal. If the permeability of the membrane is changed, Na+ ions are able to enter into the cell. The resulting change in voltage (action potential) can be used as a cellular signal.

When acetylcholine released from the axon binds to receptors on the sarcolemma, an action potential is generated, causing a depolarization on the membrane surface, and a rapid change in transmembrane potential. As the action potential travels down the transverse tubules (T-tubules – invaginations of a cell membrane which regulate cell calcium concentration), the change in voltage triggers the release of calcium ions (Ca2+) from the sarcoplasmic reticulum into the myoplasm. The released Ca2+ then binds to troponin embedded in the actin filaments and initiates the contraction process. 

Acetylcholine is rapidly broken down into acetyl and choline by the enzyme acetylcholinesterase (AChE), which is found in the synaptic cleft. This closes the channels and returns the membrane to a polarized state. Thus, allowing tropomyosin to bind to the active binding sites on actin and therefore causing the cross-bridge to detach.

Control of muscle tension

The formation of actin-myosin cross-bridges is initiated by neural impulses, which lead to the shortening of the sarcomere. As multiple sarcomeres shorten, the subsequent shortening of the muscle pulls on the bones and creates skeletal movement. The amount of tension that a muscle fiber can produce is determined by the number of cross-bridges that are formed during contraction, which is related to cross-sectional area of the muscle fiber and the frequency of neural stimulation. The more cross-bridges are formed, the more myosin heads can pull on actin, and more tension can be produced. This allows each muscle to produce varying levels of force. 

The maximal tension produced by a sarcomere occurs when actin and myosin filaments overlap to the greatest degree. If the sarcomere is stretched past its ideal resting length, there is less overlap between actin and myosin filaments, and fewer cross-bridges can be formed. Thus, fewer myosin heads can pull on actin, resulting in less muscle tension. Similarly, as the sarcomere shortens and thin filaments reach the H zone, there is less overlap between actin and myosin filaments. Since the H zone consists of mostly of myosin tails, and cross-bridges are formed by myosin heads, actin does not bind to myosin in this zone. Thus, reducing the tension produced by the myofiber. If the sarcomere is shortened even more, thin filaments start to overlap with each other, further reducing cross-bridge formation. Conversely, if the sarcomere is stretched to a point at which thick and thin filaments do not overlap at all, no cross-bridges can be formed, and no tension can be produced. However, this rarely occurs since sensory nerves, connective tissue, and accessory proteins protect the body from extreme stretching.

The force production capability of a muscle is mainly determined by the number of myofibers within the muscle that receive an action potential from the neuron innervating them. For example, lifting a light load requires only a partial activation of the muscle, whereas heavier loads require almost all myofibers to activate (near-maximum force production). This is done by increasing the frequency of action potentials (the number of signals per second), which causes tropomyosin to be flooded with calcium. 

The sarcomere is the smallest functional unit of striated muscle tissue.

Final thoughts

Muscle contraction is a result of a complex sequence of steps, where electric neural input is transformed into mechanical movement. This electrochemical process forms the foundation for all voluntary movements.

Muscle contraction occurs when sarcomeres shorten. This takes place as myosin heads form cross-bridges with actin, pulling them inwards. This cyclical process of forming and breaking cross-bridges between the two filaments requires energy from ATP, and is controlled by regulatory proteins troponin and tropomyosin. The excitation-contraction coupling phase transduces the electrical signal of the neuron to an electrical signal on the muscle membrane via a neurotransmitter – acetylcholine (ACh), which initiates force production. The amount of force produced is ultimately determined by how many muscle fibers are recruited.

Did you learn anything new about how muscles contract? Let us know in the comments below.

Sources

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  • Huxley, H. E. & Hanson, J. Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 173, 973–976 (1954) doi:10.1038/173973a0.
  • Huxley, A. F. & Niedergerke, R. Structural changes in muscle during contraction: Interference microscopy of living muscle fibres. Nature 173, 971–973 (1954) doi:10.1038/173971a0.
  • Smyrnias, I., Bootman, M.D., Roderick, H.L. (2012). Excitation–Contraction Coupling. In: Mooren, F.C. (eds) Encyclopedia of Exercise Medicine in Health and Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29807-6_71

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