Sliding filament theory

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Sliding filament theory: A sarcomere in relaxed (above) and contracted (below) positions Sarcomere.svg
Sliding filament theory: A sarcomere in relaxed (above) and contracted (below) positions

The sliding filament theory explains the mechanism of muscle contraction based on muscle proteins that slide past each other to generate movement. [1] According to the sliding filament theory, the myosin (thick filaments) of muscle fibers slide past the actin (thin filaments) during muscle contraction, while the two groups of filaments remain at relatively constant length.

Contents

The theory was independently introduced in 1954 by two research teams, one consisting of Andrew Huxley and Rolf Niedergerke from the University of Cambridge, and the other consisting of Hugh Huxley and Jean Hanson from the Massachusetts Institute of Technology. [2] [3] It was originally conceived by Hugh Huxley in 1953. Andrew Huxley and Niedergerke introduced it as a "very attractive" hypothesis. [4]

Before the 1950s there were several competing theories on muscle contraction, including electrical attraction, protein folding, and protein modification. [5] The novel theory directly introduced a new concept called cross-bridge theory (classically swinging cross-bridge, now mostly referred to as cross-bridge cycle) which explains the molecular mechanism of sliding filament. Cross-bridge theory states that actin and myosin form a protein complex (classically called actomyosin) by attachment of myosin head on the actin filament, thereby forming a sort of cross-bridge between the two filaments. The sliding filament theory is a widely accepted explanation of the mechanism that underlies muscle contraction. [6]

Sliding Filament Theory.svg
This model shows the four main and significant steps of the sliding filament theory as well as with a detailed visual. The Sliding Filament Theory Visual Model.pdf
This model shows the four main and significant steps of the sliding filament theory as well as with a detailed visual.

History

Early works

The first muscle protein discovered was myosin by a German scientist Willy Kühne, who extracted and named it in 1864. [7] In 1939 a Russian husband and wife team Vladimir Alexandrovich Engelhardt and Militsa Nikolaevna Lyubimova discovered that myosin had an enzymatic (called ATPase) property that can breakdown ATP to release energy. [8] Albert Szent-Györgyi, a Hungarian physiologist, turned his focus on muscle physiology after winning the Nobel Prize in Physiology or Medicine in 1937 for his works on vitamin C and fumaric acid. He demonstrated in 1942 that ATP was the source of energy for muscle contraction. He actually observed that muscle fibres containing myosin B shortened in the presence of ATP, but not with myosin A, the experience which he later described as "perhaps the most thrilling moment of my life." [9] With Brunó FerencStraub, he soon found that myosin B was associated with another protein, which they called actin, while myosin A was not. Straub purified actin in 1942, and Szent-Györgyi purified myosin A in 1943. It became apparent that myosin B was a combination of myosin A and actin, so that myosin A retained the original name, whereas they renamed myosin B as actomyosin. By the end of the 1940s Szent-Györgyi's team had postulated with evidence that contraction of actomyosin was equivalent to muscle contraction as a whole. [10] But the notion was generally opposed, even from the likes of Nobel laureates such as Otto Fritz Meyerhof and Archibald Hill, who adhered to the prevailing dogma that myosin was a structural protein and not a functional enzyme. [3] However, in one of his last contributions to muscle research, Szent-Györgyi demonstrated that actomyosin driven by ATP was the basic principle of muscle contraction. [11]

Origin

Structure of muscle fibre (sarcomere) under electron microscope with schematic explanation Sarcomere.gif
Structure of muscle fibre (sarcomere) under electron microscope with schematic explanation

By the time Hugh Huxley earned his PhD from the University of Cambridge in 1952 on his research on the structure of muscle, Szent-Györgyi had turned his career into cancer research. [12] Huxley went to Francis O. Schmitt's laboratory at the Massachusetts Institute of Technology with a post-doctoral fellowship in September 1952, where he was joined by another English post-doctoral fellow Jean Hanson in January 1953. Hanson had a PhD in muscle structure from King's College, London in 1951. Huxley had used X-ray diffraction to speculate that muscle proteins, particularly myosin, form structured filaments giving rise to sarcomere (a segment of muscle fibre). Their main aim was to use electron microscopy to study the details of those filaments as never done before. They soon discovered and confirmed the filament nature of muscle proteins. Myosin and actin form overlapping filaments, myosin filaments mainly constituting the A band (the dark region of a sarcomere), while actin filaments traverse both the A and I (light region) bands. [13] Huxley was the first to suggest the sliding filament theory in 1953, stating:

"… [I]f it is postulated that stretching of the muscle takes place, not by an extension of the filaments, but by a process in which the two sets of filaments slide [emphasis added] past each other; extensibility will then be inhibited if the myosin and actin are linked together." [14]

Later, in 1996, Huxley regretted that he should have included Hanson in the formulation of his theory because it was based on their collaborative work. [15]

Andrew Huxley, whom Alan Hodgkin described as "wizard with scientific apparatus", had just discovered the mechanism of the nerve impulse (action potential) transmission (for which he and Hodgkin later won the Nobel Prize in Physiology or Medicine in 1963) in 1949 using his own design of voltage clamp, and was looking for an associate who could properly dissect out muscle fibres. [16] Upon recommendation of a close friend Robert Stämpfli, a German physician Rolf Niedergerke joined him at the University of Cambridge in 1952. By then he realised that the conventionally used phase-contrast microscope was not suitable for fine structures of muscle fibres, and thus developed his own interference microscope. Between March 1953 and January 1954 they executed their research. [17] Huxley recollected that at the time the only person who ever thought of sliding filaments before 1953 was Dorothy Hodgkin (later winner of the 1964 Nobel Prize in Chemistry). [18] He spent the summer of 1953 at Marine Biological Laboratory at Woods Hole, Massachusetts, to use electron microscope there. There he met Hugh Huxley and Hanson with whom he shared data and information on their works. They parted with an agreement that they would keep in touch, and when their aim is achieved, they would publish together, if they ever "reached similar conclusions". [2]

The sliding filament theory

Diagrammatic explanation of sliding filament hypothesis Sarcomere.svg
Diagrammatic explanation of sliding filament hypothesis

The sliding filament theory was born from two consecutive papers published on the 22 May 1954 issue of Nature under the common theme "Structural Changes in Muscle During Contraction". Though their conclusions were fundamentally similar, their underlying experimental data and propositions were different.

Huxley-Niedergerke hypothesis

The first paper, written by Andrew Huxley and Rolf Niedergerke, is titled "Interference microscopy of living muscle fibres". It was based on their study of frog muscle using interference microscope, which Andrew Huxley developed for the purpose. According to them: [4]

  1. the I bands are composed of actin filaments, and the A bands principally of myosin filaments; and
  2. during contraction, the actin filaments move into the A bands between the myosin filaments.

Huxley-Hanson hypothesis

The second paper, by Hugh Huxley and Jean Hanson, is titled "Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation". It is more elaborate and was based on their study of rabbit muscle using phase contrast and electron microscopes. According to them: [19]

  1. the backbone of a muscle fibre is actin filaments which extend from the Z line up to one end of the H zone, where they are attached to an elastic component which they named "S filament";
  2. myosin filaments extend from one end of the A band through the H zone up to the other end of the A band;
  3. myosin filaments remain in relatively constant length during muscle stretch or contraction;
  4. if myosin filaments contract beyond the length of the A band, their ends fold up to form contraction bands;
  5. myosin and actin filaments lie side by side in the A band and in the absence of ATP they do not form cross-linkages;
  6. during stretching, only the I bands and H zone increase in length, while A bands remain the same;
  7. during contraction, actin filaments move into the A bands and the H zone is filled up reducing its stretch, the I bands shorten, the Z line comes in contact with the A bands; and
  8. the possible driving force of contraction is the actin-myosin linkages which depend on ATP hydrolysis by the myosin.

Reception and consequences

In spite of strong evidence, the sliding filament theory did not gain any support for several years to come. [20] Szent-Györgyi himself refused to believe that myosin filaments were confined to the thick filament (A band). [15] F.O. Schmitt, whose electron microscope provided the best data, also remained sceptical of the original images. [21] There were also immediate arguments as to the organisation of the filaments, whether the two sets (myosin and actin) of filaments were merely overlapping or continuous. It was only with the new electron microscope that Hugh Huxley confirmed the overlapping nature of the filaments in 1957. [22] It was also from this publication that the existence of actin-myosin linkage (now called cross-bridge) was clearly shown. But he took another five years to provide evidence that the cross-bridge was a dynamic interaction between actin and myosin filaments. [23] He obtained the actual molecular arrangement of the filaments using X-ray crystallography by teaming up with Kenneth Holmes, who was trained by Rosalind Franklin, in 1965. [24] It was only after a conference in 1972 at Cold Spring Harbor Laboratory, where the theory and its evidence were deliberated, that it became generally accepted. [25] At the conference, as Koscak Maruyama later recalled, Hanson had to answer the criticisms by shouting, "I know I cannot explain the mechanism yet, but the sliding is a fact." [26] The factual proofs came in the early 1980s when it could be demonstrated the actual sliding motion using novel sophisticated tools by different researchers. [27] [28] [29]

Cross-bridge mechanism

With substantial evidence, Hugh Huxley formally proposed the mechanism for sliding filament which is variously called swinging cross-bridge model, cross-bridge theory or cross-bridge model. [3] [30] (He himself preferred the name "swinging crossbridge model", because, as he recalled, "it [the discovery] was, after all, the 1960s". [2] ) He published his theory in the 20 June 1969 issue of Science under the title "The Mechanism of Muscular Contraction". [31] According to his theory, filament sliding occurs by cyclic attachment and detachment of myosin on actin filaments. Contraction occurs when the myosin pulls the actin filament towards the centre of the A band, detaches from actin and creates a force (stroke) to bind to the next actin molecule. [32] This idea was subsequently proven in detail, and is more appropriately known as the cross-bridge cycle. [33]

Related Research Articles

<span class="mw-page-title-main">Andrew Huxley</span> English physiologist and biophysicist

Sir Andrew Fielding Huxley was an English physiologist and biophysicist. He was born into the prominent Huxley family. After leaving Westminster School in central London, he went to Trinity College, Cambridge, on a scholarship, after which he joined Alan Hodgkin to study nerve impulses. Their eventual discovery of the basis for propagation of nerve impulses earned them the Nobel Prize in Physiology or Medicine in 1963. They made their discovery from the giant axon of the Atlantic squid. Soon after the outbreak of the Second World War, Huxley was recruited by the British Anti-Aircraft Command and later transferred to the Admiralty. After the war he resumed research at the University of Cambridge, where he developed interference microscopy that would be suitable for studying muscle fibres.

<span class="mw-page-title-main">Cytoskeleton</span> Network of filamentous proteins that forms the internal framework of cells

The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is composed of similar proteins in the various organisms. It is composed of three main components: microfilaments, intermediate filaments, and microtubules, and these are all capable of rapid growth or disassembly depending on the cell's requirements.

<span class="mw-page-title-main">Smooth muscle</span> Involuntary non-striated muscle

Smooth (soft) muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations. It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.

<span class="mw-page-title-main">Microfilament</span> Filament in the cytoplasm of eukaryotic cells

Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other proteins in the cell. Microfilaments are usually about 7 nm in diameter and made up of two strands of actin. Microfilament functions include cytokinesis, amoeboid movement, cell motility, changes in cell shape, endocytosis and exocytosis, cell contractility, and mechanical stability. Microfilaments are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. In inducing cell motility, one end of the actin filament elongates while the other end contracts, presumably by myosin II molecular motors. Additionally, they function as part of actomyosin-driven contractile molecular motors, wherein the thin filaments serve as tensile platforms for myosin's ATP-dependent pulling action in muscle contraction and pseudopod advancement. Microfilaments have a tough, flexible framework which helps the cell in movement.

<span class="mw-page-title-main">Cleavage furrow</span> Plasma membrane invagination at the cell division site

In cell biology, the cleavage furrow is the indentation of the cell's surface that begins the progression of cleavage, by which animal and some algal cells undergo cytokinesis, the final splitting of the membrane, in the process of cell division. The same proteins responsible for muscle contraction, actin and myosin, begin the process of forming the cleavage furrow, creating an actomyosin ring. Other cytoskeletal proteins and actin binding proteins are involved in the procedure.

<span class="mw-page-title-main">Myofibril</span> Contractile element of muscle

A myofibril is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibril has a diameter of 1–2 micrometres. They are created during embryonic development in a process known as myogenesis.

<span class="mw-page-title-main">Sarcomere</span> Repeating unit of a myofibril in a muscle cell

A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<span class="mw-page-title-main">Myosin</span> Superfamily of motor proteins

Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.

<span class="mw-page-title-main">Frank–Starling law</span> Relationship between stroke volume and end diastolic volume

The Frank–Starling law of the heart represents the relationship between stroke volume and end diastolic volume. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction, when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches cardiac muscle, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.

<span class="mw-page-title-main">Muscle contraction</span> Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

<span class="mw-page-title-main">Isotropic bands</span>

In physiology, isotropic bands are the lighter bands of skeletal muscle cells. Isotropic bands contain only actin-containing thin filaments. The thin filaments are placed between 2 myosin filaments and contain only the actin filaments of neighboring sarcomeres. Bisecting the I band and serving as an anchoring point for the two adjacent actin filaments is the Z disc. During muscle contraction, the I band will shorten, while an A band will maintain its width.

<span class="mw-page-title-main">Hugh Huxley</span> English biologist (1924–2013)

Hugh Esmor Huxley MBE FRS was a British molecular biologist who made important discoveries in the physiology of muscle. He was a graduate in physics from Christ's College, Cambridge. However, his education was interrupted for five years by the Second World War, during which he served in the Royal Air Force. His contribution to development of radar earned him an MBE.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">Myosin light-chain kinase</span> Class of kinase enzymes

Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II.

<span class="mw-page-title-main">Jean Hanson</span> British zoologist and biophysicist

Emmeline Jean Hanson was a biophysicist and zoologist known for her contributions to muscle research. Hanson gained her PhD in zoology from Bedford College, University of London before spending the majority of her career at a biophysics research unit at King's College London, where she was a founder member, and later its second Head. While working at Massachusetts Institute of Technology, she, with Hugh Huxley, discovered the mechanism of movement of muscle fibre in 1954, which came to known as "sliding filament theory". This was a groundbreaking research in muscle physiology, and for this BBC nicknamed her "Mrs Muscle" on the 50th anniversary of the discovery.

Rolf Nidergerke was a German physiologist and physician, and one of the discoverers of the sliding filament theory of muscle contraction. He and Andrew Huxley, complimenting the independent works of Hugh Huxley and Jean Hanson, revealed that muscle contraction is due to shortening of the muscle fibres. He studied medicine throughout the Second World War, and obtained his MD degree as the war ended in 1945. After a brief practise in his hometown, he chose a research career. He became associated with Huxley, whom he joined at Cambridge University. Together they published a landmark paper in Nature in 1954, which became the foundation of muscle mechanics.

<span class="mw-page-title-main">Ilona Banga</span> Hungarian biochemist

Ilona Banga (1906–1998) was a Hungarian biochemist known for co-discovering actomyosin and working to characterize how actin and myosin interact to produce muscle contraction. She and her husband József Mátyás Baló discovered the first elastase – an enzyme capable of degrading the protein elastin which gives tissues like veins their flexibility. She also contributed to work that earned Albert Szent-Györgyi the Nobel Prize in Physiology or Medicine in 1937, including by developing methods for the purification and characterization of large quantities of vitamin C. During World War II she saved the equipment of the Institute of Chemistry of the University of Szeged.

Edwin W. Taylor is an adjunct professor of cell and developmental biology at Northwestern University. He was elected to the National Academy of Sciences in 2001. Taylor received a BA in physics and chemistry from the University of Toronto in 1952; an MSc in physical chemistry from McMaster University in 1955, and a PhD in biophysics from the University of Chicago in 1957. In 2001 Taylor was elected to the National Academy of Scineces in Cellular and Developmental Biology and Biochemistry.

Hans Hermann Julius Wilhelm Weber was a German physiologist and biochemist who worked on muscle structure and function. He was among the pioneers who helped establish the mechanism of muscle relaxation and contraction. His daughter Annemarie Weber also continued work in myosin biochemistry.

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