Chapter 2: How Skeletal Muscle Contracts

Chapter 1 described the parts. This chapter puts them in motion: how a nerve impulse becomes a rise in calcium, how calcium lets myosin grab actin, how ATP drives each stroke and each release, and how the muscle relaxes again. It ends with where the ATP comes from and with four clinical situations that make sense once the mechanism is clear.

The session summarized the whole sequence as a chain of five links:

1. Events at the neuromuscular junction: the nerve signal crosses to the muscle fiber.
2. Excitation–contraction coupling: the muscle action potential is turned into a calcium signal.
3. The Ca²⁺ signal unlocks the thin filament.
4. The contraction–relaxation cycle of the crossbridges.
5. The results you can measure: a muscle twitch, explained by the sliding filament theory.

Events at the neuromuscular junction

Skeletal muscle never contracts on its own; each fiber waits for its motor neuron. The neuromuscular junction (NMJ) is the synapse where the axon terminal of a somatic motor neuron meets the fiber's motor end plate, a specialized, deeply folded patch of sarcolemma.

1. An action potential reaches the axon terminal and opens voltage-gated Ca²⁺ channels in the terminal membrane.
2. Ca²⁺ entry triggers exocytosis of synaptic vesicles, releasing acetylcholine (ACh) into the synaptic cleft.
3. ACh diffuses across the cleft and binds nicotinic ACh receptors on the motor end plate. These are ligand-gated cation channels.
4. The channels let Na⁺ in (and some K⁺ out). The net inward current depolarizes the end plate: the end-plate potential.
5. The end-plate potential is large enough to reach threshold in the neighboring sarcolemma every time (the NMJ has a big "safety factor"), so a muscle action potential fires and spreads along the whole fiber.
6. Acetylcholinesterase in the cleft breaks ACh down within milliseconds, so one nerve impulse causes one muscle action potential.

In the practicum, an electrical stimulator takes the place of the nerve and ACh: the current depolarizes the membrane directly to threshold.

The all-or-none principle

A single muscle fiber obeys the all-or-none law: a stimulus below threshold produces no contraction, and any stimulus at or above threshold produces a full action potential and a full twitch of that fiber. Stronger stimuli do not make one fiber contract harder. A whole muscle can still grade its force because it contains many fibers with different thresholds, as Chapter 3 explains.

Clinical links at the NMJ.

• Myasthenia gravis: autoantibodies destroy nicotinic receptors, so end-plate potentials shrink and muscles tire with repeated use (drooping eyelids by evening, double vision). Treated with acetylcholinesterase inhibitors such as pyridostigmine.
• Botulinum toxin blocks ACh release, causing flaccid paralysis. In tiny doses it is used for spasticity, dystonia and cosmetic purposes.
• Organophosphate poisoning inhibits acetylcholinesterase: ACh accumulates, first causing twitching (fasciculations), then paralysis.
• Neuromuscular blocking drugs (such as rocuronium) block the receptors and are used to relax muscles during surgery.

Excitation–contraction coupling

Excitation–contraction coupling is the sequence that links the electrical event at the sarcolemma to the mechanical event in the myofibrils. The link is calcium.

Following the numbers in the diagram:

1. A nerve action potential reaches the motor neuron terminal.
2. ACh is released and binds nicotinic receptors on the motor end plate.
3. The end-plate potential triggers a muscle action potential that spreads along the sarcolemma.
4. The action potential travels down the T-tubules into the depth of the fiber.
5. In the T-tubule membrane, dihydropyridine (DHP) receptors, which are L-type Ca²⁺ channels acting as voltage sensors, change shape. In skeletal muscle each DHP receptor is mechanically linked to a ryanodine receptor (RyR1), the Ca²⁺ release channel of the neighboring terminal cisterna, and pulls it open.
6. Ca²⁺ pours out of the SR down its steep concentration gradient. Cytosolic Ca²⁺ rises about a hundredfold, from roughly 0.1 µM to around 10 µM.
7. Ca²⁺ binds troponin C, the thin filament is switched on, and the crossbridge cycle begins.
8. As soon as the action potential ends, SERCA pumps (sarco/endoplasmic reticulum Ca²⁺-ATPases) start pumping Ca²⁺ back into the SR, which leads to relaxation.

Skeletal and cardiac coupling differ. The textbook figure used in the session (reproduced in this section) is labeled for cardiac muscle. There, the L-type channel lets a small amount of extracellular Ca²⁺ in, and that Ca²⁺ opens the ryanodine receptors (calcium-induced calcium release, producing local "Ca²⁺ sparks"). During relaxation, cardiac cells also remove Ca²⁺ through the Na⁺/Ca²⁺ exchanger (NCX), whose Na⁺ gradient is maintained by the Na⁺/K⁺-ATPase. In skeletal muscle the coupling is mechanical: the DHP receptor opens RyR1 directly, and skeletal muscle can contract even with no Ca²⁺ in the extracellular fluid. For both, the core logic is the same: electrical signal → Ca²⁺ release from the SR → Ca²⁺ binds troponin.

Calcium switches on the thin filament

At rest, tropomyosin lies over the myosin-binding sites on actin, and the myosin heads, already "cocked" with ADP and Pi bound, cannot attach. When Ca²⁺ arrives:

1. Cytosolic Ca²⁺ rises.
2. Ca²⁺ binds troponin C.
3. The troponin–Ca²⁺ complex changes shape and pulls tropomyosin away from the binding sites on actin.
4. Myosin heads bind actin and complete a power stroke.
5. The actin filament moves toward the center of the sarcomere.

As long as Ca²⁺ stays bound to troponin, the sites stay exposed and the cycle repeats.

The crossbridge cycle

The crossbridge cycle is the repeating attach–pull–release–recock sequence of a myosin head. The session stressed that the cycle is conventionally described starting from the rigor state (fase rigor/kaku) and that ATP has two separate jobs in it.

Step by step:

1. Rigor state. The myosin head is tightly bound to actin at about 45° to the filaments, with no ATP or ADP attached. In living muscle this state lasts only an instant.
2. ATP binds to the head. This lowers myosin's affinity for actin, and the head detaches.
3. ATP is hydrolyzed by the head's ATPase into ADP and Pi, which both stay bound. The energy released cocks the head to about 90°, like pulling back a spring. The cocked head binds weakly to a new actin molecule further along, provided Ca²⁺ has uncovered the site.
4. Release of Pi triggers the power stroke. The head swings back toward 45°, pulling the thin filament toward the M line. At the end of the stroke ADP is released, and the head is back in the tightly bound rigor state, ready for another ATP.

The heads cycle asynchronously: at any moment some are attached and pulling while others are detaching or recocking, the way a team hauls a rope hand over hand. This is why force is smooth rather than jerky and why the filament never slips back.

ATP is used three times in each contraction–relaxation:

A fourth, indirect use is the Na⁺/K⁺-ATPase, which restores the ion gradients that make the next action potential possible.

The sliding filament theory

The sliding filament theory (Huxley and Hanson; Huxley and Niedergerke, 1954) states that muscle shortens because thin filaments slide over thick filaments, not because either filament gets shorter. The evidence is the band pattern described in Chapter 1: during contraction the A band keeps its length while the I band and H zone narrow and the Z discs move closer together.

Each crossbridge stroke moves a thin filament only about 10 nm, but there are billions of heads cycling many times per second, and thousands of sarcomeres in series along each myofibril. The small steps add up to centimeters of shortening at the whole-muscle level.

Relaxation

Relaxation is an active process too:

1. The motor neuron stops firing, ACh is destroyed by acetylcholinesterase, and the sarcolemma repolarizes.
2. The DHP receptors return to their resting shape and the ryanodine receptors close.
3. Ca²⁺ unbinds from troponin as the cytosolic concentration falls.
4. SERCA pumps Ca²⁺ back into the SR, using ATP. Inside the SR, the protein calsequestrin binds Ca²⁺ so a large store can be held at a manageable free concentration.
5. Tropomyosin slides back over the binding sites; crossbridges can no longer form, and the elastic elements (titin, connective tissue) return the muscle to its resting length.

In the session's diagram (steps 7–10) these are labeled: Ca²⁺ unbinds from troponin (7), Ca²⁺ is pumped back into the SR (8), Ca²⁺ is exchanged for Na⁺ by the NCX (9), and the Na⁺ gradient is maintained by the Na⁺/K⁺-ATPase (10). Steps 9 and 10 are the main extra route in cardiac muscle; in skeletal muscle SERCA does almost all of the work.

Energy for contraction

A muscle fiber holds only enough ATP for a few seconds of hard work, yet it can keep contracting for hours. It manages this with three pathways that regenerate ATP at different speeds.

The timeline from the session puts them in order during a single effort: stored ATP is used first (≈6 s), creatine phosphate takes over (≈10 s), then glycogen is broken down by glycolysis (to ≈30–40 s and until the end of a short, intense bout). In prolonged exercise, most ATP comes from aerobic breakdown of several fuels.

Two practical consequences follow:

• Speed versus capacity. The anaerobic systems are fast but small; the aerobic system is large but slow to ramp up and limited by oxygen delivery. That is why nobody can sprint for a whole marathon.
• Recovery oxygen uptake. After intense exercise, breathing stays deep and fast because extra oxygen is needed to rebuild creatine phosphate and ATP, reload myoglobin and clear lactate (the "oxygen debt", now called excess post-exercise oxygen consumption, EPOC).

Fiber types

Individual fibers are specialized for one pathway or another:

Every muscle is a mixture; training shifts the balance.

Clinical correlations

Hypertrophy

Muscle hypertrophy is an increase in muscle size because each fiber makes more actin and myosin (more myofibrils). It follows regular, high-intensity resistance exercise of short duration that relies mainly on anaerobic (glycolytic) metabolism, such as weightlifting. Hormones (testosterone, growth hormone, insulin-like growth factor 1) promote it. In adults the number of fibers barely changes; the fibers get thicker. Endurance training, by contrast, increases mitochondria, capillaries and myoglobin more than size.

Atrophy

Muscle atrophy is a loss of actin and myosin, so muscles become smaller and weaker. It has three common causes:

• Disuse: prolonged bed rest, immobilization in a cast, or long-term hospitalization. Measurable loss begins within days.
• Denervation: if the motor nerve is damaged, the muscle no longer contracts and wastes rapidly (for example after a peripheral nerve injury, or in poliomyelitis). Without reinnervation the fibers are eventually replaced by fibrous and fatty tissue.
• Aging (sarcopenia): a gradual loss of muscle mass and strength from middle age onward, a major cause of falls and frailty.

Rigor mortis

Rigor mortis is the stiffening of muscles after death. After death, Ca²⁺ leaks out of the SR and from the extracellular fluid, so crossbridges form. But no new ATP is produced, so the heads cannot detach: every crossbridge is frozen in the rigor state (step 1 of the cycle). It is a predictable physiological process, not a disease. It begins a few hours after death, is fully developed at about 12 hours, and fades over the next day or two as the muscle proteins are broken down. Forensic examiners use its stage to help estimate the time of death.

Muscle cramp ("charley horse")

A cramp is a sudden, involuntary, sustained and painful contraction, usually of the calf. It arises from hyperexcitability of the somatic motor neurons supplying the muscle, which fire repeatedly and produce a tetanic contraction. Cramps last from seconds to minutes and are relieved by stretching the muscle, which activates inhibitory reflexes (the Golgi tendon organ, Chapter 4). Common triggers are electrolyte imbalance and heavy sweating, dehydration and fatigue after unaccustomed exercise.

Key points

• Contraction follows five links: NMJ transmission → excitation– contraction coupling → Ca²⁺ signal → crossbridge cycle → twitch.
• ACh opens nicotinic receptors at the motor end plate; the end-plate potential always triggers a muscle action potential. A single fiber is all-or-none.
• In skeletal muscle, the T-tubule DHP receptor is mechanically coupled to RyR1 on the SR; Ca²⁺ is released, binds troponin C, and tropomyosin moves off actin's binding sites.
• Crossbridge cycle: rigor → ATP binds, head detaches → ATP hydrolyzed, head cocks → Pi release, power stroke → ADP release, rigor again.
• ATP powers the stroke, detaches myosin and drives SERCA. No ATP means rigor; no SERCA activity means no relaxation.
• Filaments slide; they do not shorten.
• ATP comes from stored ATP (seconds), creatine phosphate (≈10–15 s), anaerobic glycolysis (2 ATP per glucose, ≈30–40 s) and aerobic respiration (≈32 ATP per glucose, hours).
• Hypertrophy = more actin and myosin; atrophy = loss of them (disuse, denervation, sarcopenia); rigor mortis = no ATP to break crossbridges; cramp = motor neuron hyperexcitability, relieved by stretching.