Muscle Contraction: Regulation


Remarkably we can tell our arms or legs to move and they do it. We can directly control or regulate the activity of our skeletal muscles. Striated muscle movement, produced by the interaction of filaments containing the proteins myosin and actin, is regulated by the proteins tropomyosin and troponin on the actin filaments. When an electrical signal passes down the motor nerve to a muscle it triggers a depolarisation of the muscle membrane (sarcolemma). In turn this triggers the sarcoplasmic reticulum to release calcium ions into the muscle interior where they bind to troponin, thus causing tropomyosin to shift from the face of the actin filament to which myosin heads need to bind to produce contraction. During relaxation calcium is pumped back into the sarcoplasmic reticulum, troponin loses its calcium and tropomyosin reverts to its off position. This is the steric blocking mechanism of muscle regulation.

Key Concepts:

  • Striated muscles contain repeating sarcomeres of overlapping arrays of long, thin actin and thicker myosin filaments.

  • Myosin filaments carry projections, the myosin heads, which are enzymes that can bind to actin and can split and make use of the energy from ATP.

  • During muscle contraction myosin heads bind to actin, change their configuration on actin along with releasing the products of ATP hydrolysis and cause relative sliding of the actin and myosin filaments.

  • Vertebrate striated muscle contraction is controlled (regulated) by the action of the proteins troponin and tropomyosin on the actin filaments.

  • Nervous stimulation causes a depolarisation of the muscle membrane (sarcolemma) which triggers the release of calcium ions from the sarcoplasmic reticulum.

  • Calcium ions bind to troponin and thus cause or allow the tropomyosin strands on the actin filament to move so that the part of the actin surface where myosin heads need to bind is uncovered.

  • Contraction (force generation) then occurs and only stops when the sarcoplasmic reticulum pumps calcium out of the muscle interior, troponin loses its bound calcium and tropomyosin shifts back to its off position.

Keywords: myosin; actin; crossbridge cycle; tropomyosin; troponin; ryanodine receptor; steric blocking model

Figure 1.

(a) The structure of the sarcomere repeating unit in vertebrate striated muscles. One sarcomere, from Z‐line (Z) to Z‐line, is about 2.3–2.5 μm in rest‐length muscles. The sarcomere consists of a central set of bipolar myosin filaments with projections (myosin heads) on their surface. These filaments define the A‐band of the muscle sarcomere. Halfway along their length, the myosin filaments in the A‐band are linked by a bridging structure known as the M‐band. Partly overlapping the myosin filaments are two sets of actin filaments, which link through the Z‐line to actin filaments in the next sarcomeres. (b) Simple four‐state scheme of the myosin (ATPase) cycle when activated by actin. The AM state, with myosin heads rigidly bound to actin, occurs in the absence of adenosine triphosphate (ATP) and is the state that develops after death when the supply of ATP comes to an end. Addition of ATP (step 1) brings the heads off actin to give separate A and M.ATP moieties. The M.ATP then hydrolyses to M.ADP.Pi (step 2) with the products adenosine disphosphate (ADP) and inorganic phosphate (Pi) remaining bound to the myosin heads. Myosin in the M.ADP.Pi state can reattach to actin (step 3), after which the products Pi and then ADP are released in the step thought to be associated with the development of mechanical force (step 4). If the muscle is free to shorten, then step 4 is where this will happen.

Figure 10.

Three stereo views of a three‐dimensional reconstruction at 2.7 nm resolution of the ryanodine receptor (RyR or Ca2+ release channel) from skeletal muscle in its open state. The distance across this face is approximately 28 nm. The reconstruction was carried out by single‐particle analysis and angular reconstitution of RyR images in electron micrographs, and the open state was obtained by incubation of the RyR in 100 mol L−1 Ca2+ and 100 nmol L−1 ryanodine for 3 h at 20°C. (a) The flat squarish face of the RyR, thought to be pointing towards the transverse tubules. (b) A side view, with the membrane‐dwelling part protruding below the sarcoplasmic face. (c) The same reconstruction as viewed from inside the terminal cisternae of the sarcoplasmic reticulum. Courtesy of E.V. Orlova, Imperial College, London.

Figure 2.

Stereo view of the structure of the myosin head as determined by Rayment et al. using protein crystallography. This is a ribbon diagram showing the protein polypeptide backbone only, not the amino acid side‐chains. The top half of the structure is the motor domain, which contains the ATP‐binding site and the actin‐binding face (top left). The lower half of the structure is commonly known as the neck or lever arm. This consists of a long α‐helical part of the myosin heavy chain (blue/purple) which links back to the myosin rod at the bottom end of the structure (beyond residue 843), around which are clamped two light chains, the essential light chain (yellow) and the regulatory light chain (pink/mauve). The force‐generating cycle is thought to involve an ATP‐driven change in angle at a hinge region between the motor domain and the lever arm. Reprinted with permission from Rayment et al. . Copyright © 1993 American Association for the Advancement of Science.

Figure 3.

(a) Ribbon diagram of the actin monomer structure as determined by Kabsch et al. using protein crystallography. Note the existence of discrete subdomains: 1 (red), 2 (green), 3 (blue) and 4 (yellow). (b) Ribbon diagram of the actin monomer in (a) arranged to form the actin filament by Holmes et al. . (c) Ribbon diagram of the two‐chain coiled‐coil α‐helical structure of tropomyosin, which is approximately 40 nm long. (d) Model of the troponin complex, drawn to the same scale as (a)–(c), including the known structure of troponin C, shown as a ribbon diagram (Herzberg and James, ). The rest of the oval‐shaped head is troponin I and part of troponin T. The remainder of troponin T forms the rod‐like tail of the complex. Figure c and d reproduced with permission from Squire and Morris Copyright © 1998 FASEB.

Figure 4.

Docking of troponin and tropomyosin structures onto actin. A three‐dimensional density map of the muscle thin filament determined by electron microscopy and single particle analysis is shown as a wire mesh. An actin atomic model (Holmes et al., ) has been docked into the three‐dimensional map (Cα atoms in blue). The map has been rotated by −80° about the filament axis in (a) and (d) and by −40° in (b) and (e) with respect to the position shown in (c) and (f). (a)–(c), space‐filling models of the partial troponin crystal structure (Vinogradova et al., ) (displayed in magenta, PDB code 1yv0), and the tropomyosin crystal structure (displayed in yellow, PDB code 1c1g) are docked into the electron density envelope. (d)–(f) Troponin and tropomyosin are displayed as ribbon diagrams: parts of the three troponin components are displayed in different colors Tn‐C, green; Tn‐T, pink and Tn‐I, cyan. Unassigned density (yellow arrows) running alongside tropomyosin can be seen in (b) and (e). The barbed and pointed ends are towards the Z‐line and M‐band, respectively. Reproduced from Paul et al. , with permission from the American Society for Biochemistry and Molecular Biology.

Figure 5.

Two interleaved stereo views of the actin filament in the Ca2+‐free ‘off’ state (A) and on the ‘on’ state (B) with Ca2+ ions bound. The change that occurs is a movement of tropomyosin from being close to subdomain 1 (dark red, arrowed) of actin in (A) to being much further from subdomain 1 in (B). It is to subdomain 1 that the myosin heads need to bind to complete their ATPase cycle. Reproduced with permission from Squire and Morris Copyright © 1998 FASEB.

Figure 6.

Schematic illustrations of different possible thin filament regulation schemes as discussed in the text. In (a) the tropomyosin has three distinct positions on the actin filament. In (b) the tropomyosin has only two defined states, ‘blocked’ and ‘open’, but the equilibrium between them varies according to conditions. Without head attachment, the effect of Ca2+ binding to troponin is to shift the equilibrium from almost purely locked to a mixture (rapid equilibrium) of locked and open states. The addition of strongly bound heads shifts the equilibrium to almost fully open. In (c) a major effect of Ca2+ binding is to modify troponin, possibly with some slight tropomyosin movement as well, thus freeing tropomyosin so that it can move (i.e. it is unlocked). However, it takes head binding to shift tropomyosin substantially to the open position (i.e. actually to open the door). Red circles, actin monomers; long white rods, tropomyosin; ball and stick shape, troponin and orange shapes, myosin heads. Reproduced with permission from Squire and Morris Copyright © 1998 FASEB.

Figure 7.

(a) Diagram showing the innervation of a very small motor unit of muscle fibres by a single axon. In fact there may be many more fibres in a single motor unit and they need not be adjacent to one another. From Squire , after Aidley . (b) Schematic diagram of a motor endplate at the neuromuscular junction showing the incoming axon surrounded by a membranous wrapping (the myelin sheath; my), the sarcoplasm (s), the cell nuclei (mn) and the myofibrillar material made up of repeating sarcomeres (see Figure ). (c) Diagram showing the arrangement of the sarcoplasmic reticulum around myofibrils in a vertebrate skeletal muscle. The transverse tubules (ts) form the T system and they interact with the terminal cisternae (tc) of the sarcoplasmic reticulum where the calcium release channels (ryanodine receptors) are located (see Figure and Figure ). The rest of the sarcoplasmic reticulum consists of longitudinal vesicles (lv) and the fenestrated collar (fc). Reproduced from Peachey by copyright permission of The Rockerfeller University Press. (d) Variation of muscular tension (T) and myofibrillar ATPase as functions of the concentration of calcium ions. Both follow sigmoid curves (thus indicating cooperativity) centred on a calcium ion concentration of between 10−7 and 10−6 mol L−1. From Squire , after Hellam and Podolsky and Weber and Herz .

Figure 8.

(a) and (b) Complementary en face views illustrating the gross organisation of the sarcotubular system in the slow (red) fibres of a teleost fish (roach, Rutilus rutilus). This is illustrated using two kinds of electron microscopy specimen: stained sections (a) and (c) and metal‐coated freeze–fracture surfaces (b) and (d). Seen clearly in (a) are the transverse tubules (tt), terminal cisternae (tc), longitudinal vesicles (or tubules; lt) and the fenestrated collar (fc), where their location can be determined relative to the muscle Z‐line and M‐band (cf. Figure ). Glycogen granules can also be seen. The sarcoplasmic (or endoplasmic) and protoplasmic faces of the sarcoplasmic reticulum (SR) membrane appear, respectively, as convex and concave surfaces when (b) is viewed from the right‐hand side. The endoplasmic and protoplasmic faces show low and high numbers, respectively, of intramembranous particles, giving rise to smooth and rough surface appearances in (b) and (d). (c) Longitudinal section parallel to the long axis of a triad showing closely opposed tc and tt membranes to be linked periodically by electron‐dense bridges (arrowheads: identified as the Ca2+ release channels or ryanodine receptors) (see Figure ). (d) Freeze–fracture illustrating the numerous intramembranous particles (*) associated with the protoplasmic (internal) face of the SR membrane. (a) and (b) Bar, 500 nm; (c) and (d) bar, 100 nm. Reprinted from Luther et al. Copyright © 1995, with permission of Elsevier Science.

Figure 9.

Different forms of innervation in muscle fibres: (a) uniterminal (e.g. vertebrate twitch fibres), (b) multiterminal (e.g. vertebrate tonic fibres) and (c) multiterminal and polyneuronal (e.g. some invertebrate fibres). From Squire , after Aidley .



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Further Reading

Bagshaw CR (1993) Muscle Contraction, 2nd edn. London: Chapman and Hall.

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McMahon TA (1984) Muscles, Reflexes and Locomotion. Princeton, NJ: Princeton University Press.

Squire JM (1986) Muscle: Design, Diversity and Disease. Menlo Park, CA: Benjamin/Cummings.

Squire JM (1997) Architecture and function in the muscle sarcomere. Current Opinion in Structural Biology 7: 247–257.

Squire JM and Parry DAD (2005) Muscle & Molecular Motors. Advances in Protein Chemistry 71. San Diego, CA: Elsevier.

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Squire, John M(Oct 2010) Muscle Contraction: Regulation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000674.pub2]