The Chemistry of Muscle Contraction

Every movement you make — blinking, breathing, typing, sprinting — depends on protein molecules pulling on one another, powered by ATP and switched on and off by calcium ions. Muscle contraction is one of the clearest examples in biology of chemical energy being turned directly into mechanical work by molecules. This article follows the process from the structure of a muscle fibre down to a single molecular “power stroke”.

From muscle to molecule

Skeletal muscle is organised in a hierarchy:

1. A muscle is made of bundles of muscle fibres — long cells, each with many nuclei.
2. Each fibre is packed with myofibrils, rods about 1–2 µm across.
3. Each myofibril is a chain of repeating units called sarcomeres, about 2–3 µm long. The sarcomere is the basic unit of contraction.
4. Each sarcomere contains overlapping protein filaments:
   • Thick filaments, made mainly of myosin.
   • Thin filaments, made mainly of actin, plus the regulatory proteins tropomyosin and troponin.

The regular overlapping arrangement of thick and thin filaments gives skeletal muscle its striped (striated) appearance under a microscope. The thin filaments are anchored at each end of the sarcomere to a structure called the Z-line.

The sliding filament model

In the 1950s, two independent teams — Hugh Huxley with Jean Hanson, and Andrew Huxley with Rolf Niedergerke — showed that when a muscle contracts, the filaments themselves don’t shorten. Instead, the thin filaments slide past the thick filaments towards the centre of the sarcomere, pulling the Z-lines closer together. Each sarcomere shortens a little, and thousands in series shorten the whole muscle.

What makes them slide is the interaction between myosin heads and actin.

The molecules

Myosin: the motor

Myosin II, the muscle form, is a large protein made of six chains. It has a long, rod-like tail (a coiled coil of two α-helices) and two globular heads. Hundreds of myosin molecules bundle tail-to-tail to form a thick filament, with their heads sticking out towards the surrounding thin filaments. Each head has:

• an actin-binding site, and
• an ATP-binding site that is also an ATPase — an enzyme that hydrolyses ATP.

So myosin is both a structural protein and an enzyme — a nice bridge between fibrous and globular proteins.

Actin: the track

Actin exists as small globular units (G-actin) that polymerise into a long, twisted double-stranded filament (F-actin), like two strings of beads wound around each other. Each actin unit has a binding site for a myosin head.

Tropomyosin and troponin: the switch

• Tropomyosin is a long, thin protein lying along the groove of the actin filament. At rest, it covers the myosin-binding sites on actin.
• Troponin is a small complex of three proteins attached to tropomyosin at regular intervals. One part, troponin C, can bind calcium ions.

The cross-bridge cycle

When the binding sites on actin are uncovered, each myosin head goes through a repeating cycle, powered by ATP:

1. Attachment: a myosin head, carrying ADP and phosphate from a previous ATP hydrolysis, is in a “cocked”, high-energy position. It binds to actin, forming a cross-bridge.
2. Power stroke: the phosphate is released. This triggers the head to pivot, pulling the actin filament about 5–10 nm towards the centre of the sarcomere. ADP is then released.
3. Detachment: a new ATP molecule binds to the myosin head. This reduces myosin’s affinity for actin, and the head lets go.
4. Re-cocking: myosin hydrolyses the ATP to ADP and phosphate (both stay bound). The energy released changes the head’s shape, returning it to the cocked position, ready to bind actin further along.

ATP + H₂O → ADP + Pᵢ (ΔG in cells about −50 kJ mol⁻¹; see ATP vs ADP)

Each cycle uses one ATP per head. Many heads cycle independently and out of step, so at any moment some are attached while others are resetting — like a team pulling on a rope hand over hand. This keeps the filament from slipping back.

Notice the specific role of ATP: its binding causes detachment, and its hydrolysis re-cocks the head. The power stroke itself is triggered by phosphate release. This is a common misunderstanding — ATP isn’t “burned” during the pull itself.

The calcium switch

What starts and stops the cycle? Calcium ions.

1. A nerve impulse arrives at the neuromuscular junction and releases acetylcholine, which triggers an electrical signal (action potential) that spreads across the muscle fibre and down tubes (T-tubules) into the cell (see nerve impulses).
2. The signal causes the sarcoplasmic reticulum — a network of membrane sacs surrounding the myofibrils — to release stored Ca²⁺ into the cytoplasm. Calcium concentration rises roughly a hundredfold, from about 10⁻⁷ to about 10⁻⁵ mol dm⁻³.
3. Ca²⁺ binds to troponin C. Troponin changes shape and pulls tropomyosin away from the binding sites on actin.
4. Myosin heads can now bind, and the cross-bridge cycle runs. The muscle contracts.

Relaxation

When nerve signals stop, calcium pumps (Ca²⁺-ATPases) in the sarcoplasmic reticulum membrane pump Ca²⁺ back into storage, using ATP. With calcium removed from troponin, tropomyosin slides back over the binding sites, cross-bridges can’t form, and the muscle relaxes.

So ATP is needed for both contraction (the cross-bridge cycle) and relaxation (calcium pumping and myosin detachment). Calcium is the on–off switch that links the nerve signal to the chemistry — a process called excitation–contraction coupling (see calcium and bones for calcium’s other roles).

Rigor mortis: what happens without ATP

After death, cells stop making ATP. Calcium leaks out of the sarcoplasmic reticulum and binding sites on actin are exposed. Myosin heads bind to actin — but with no ATP to bind, they can’t detach. The cross-bridges lock in place, and muscles become stiff. This is rigor mortis, typically beginning a few hours after death. It eventually passes as the muscle proteins themselves begin to break down. It’s a dramatic demonstration that ATP binding is what releases myosin from actin.

Energy supply

A muscle’s ATP stock lasts only a few seconds of intense work, so it must be regenerated continuously by phosphocreatine, glycolysis and aerobic respiration (see what happens chemically when you exercise). About three-quarters of the energy released ends up as heat rather than work — which is why shivering (rapid, involuntary contraction) warms you up.

Cramps, fatigue and a note on smooth and heart muscle

• Cramps are involuntary, sustained contractions. Their causes aren’t fully understood; theories include over-excitable nerves in fatigued muscles and, in some cases, disturbed electrolytes (see electrolytes in the body).
• Fatigue during intense exercise involves accumulating phosphate, changes in calcium release and other factors (see lactic acid myths).
• Heart muscle uses the same actin–myosin–troponin system, but more of its calcium enters from outside the cell. Drugs that alter calcium handling can change the force of the heartbeat.
• Smooth muscle (in the gut and blood vessels) also uses actin and myosin, but it’s regulated differently: calcium binds a protein called calmodulin, which activates an enzyme that phosphorylates myosin.

Common misconceptions

• “The filaments shorten when a muscle contracts.” They slide; their lengths stay the same.
• “ATP is used in the power stroke.” ATP binding causes detachment, and its hydrolysis re-cocks the head; the stroke follows phosphate release.
• “Relaxation is passive.” It needs ATP to pump calcium back and detach myosin.
• “Muscles can push.” Muscles can only pull; opposing muscle pairs produce movement in both directions.

Key takeaways

• Sarcomeres contain thick (myosin) and thin (actin) filaments that slide past each other.
• Myosin heads are ATPases that run a cross-bridge cycle: attach, power stroke, detach (ATP binds), re-cock (ATP hydrolysed).
• Ca²⁺ released from the sarcoplasmic reticulum binds troponin, moving tropomyosin to expose binding sites on actin.
• Relaxation requires ATP to pump Ca²⁺ back; without ATP, muscles lock in rigor mortis.