Muscular System

An action potential in an α-motor neuron reaches the neuromuscular junction. There, voltage-gated (P/Q-type) Ca²⁺ channels open and synaptic vesicles release acetylcholine (ACh). ACh binds nicotinic receptors (ligand-gated cation channels) on the motor end plate, producing a large end-plate potential that always reaches threshold. Voltage-gated Na⁺ channels then fire a muscle action potential, which spreads along the sarcolemma and down the T-tubules. Acetylcholinesterase in the synaptic cleft stops the signal by hydrolysing ACh.

At each triad, voltage-sensing dihydropyridine receptors (DHPR, Caᵥ1.1) in the T-tubule are mechanically linked to ryanodine receptors (RyR1) in the sarcoplasmic reticulum (SR). Depolarisation therefore opens RyR1 directly, with no need for Ca²⁺ entry from outside the cell. This is unlike cardiac muscle, which relies on Ca²⁺-induced Ca²⁺ release. Cytosolic Ca²⁺ rises from ≈0.1 µM about a hundred-fold. Ca²⁺ binds troponin C, and the troponin complex moves tropomyosin away from the myosin-binding sites on actin, allowing cross-bridges to form. Relaxation needs ATP: SERCA pumps return Ca²⁺ to the SR, where calsequestrin stores it.

When a muscle contracts, the filaments do not shorten. Thin filaments slide past thick filaments toward the M line, pulling the Z discs closer together. The I band and H zone narrow, while the A band (the length of the thick filament) stays the same width.

The cross-bridge cycle has four main steps. (1) The energised myosin head, carrying ADP + Pᵢ, binds an exposed actin site. (2) Release of Pᵢ triggers the power stroke: the lever arm swings and moves the thin filament ≈5–10 nm toward the M line, after which ADP is released. (3) A new ATP binds and the head detaches from actin. (4) Myosin ATPase hydrolyses the ATP and re-cocks the head. The cycle continues for as long as Ca²⁺ and ATP are available. Without ATP, heads stay locked to actin: this is rigor mortis, which starts ≈2–6 h after death and passes after ≈1–3 days as the proteins break down.

A motor unit is one α-motor neuron and all the muscle fibres it supplies. All fibres in the unit are the same type and contract together (the all-or-none principle at unit level). Muscles that need fine control have small units, such as ≈10 fibres per neuron in the extraocular muscles. Muscles built for power have large units, up to ≈2,000 fibres in gastrocnemius.

Force is graded in two ways. Recruitment follows Henneman's size principle: small motor neurons supplying slow, fatigue-resistant fibres are recruited first, and large neurons supplying fast, powerful fibres join later. Rate coding is the second mechanism. Twitches that arrive before relaxation is complete add together (summation), giving unfused tetanus and then fused (complete) tetanus, because each extra action potential keeps cytosolic Ca²⁺ high. Normal voluntary contraction is asynchronous, sub-tetanic firing of many units, which is why it is smooth. Constant low-level activity maintains muscle tone.

Fibre types are classified by their myosin heavy-chain isoform and their metabolism.

Type I (slow oxidative) fibres look red because they contain abundant myoglobin, mitochondria and capillaries. Their myosin ATPase is slow, they produce low force, and they resist fatigue. They are supplied by small motor neurons. Postural muscles such as soleus are mostly type I.

Type IIa (fast oxidative–glycolytic) fibres are fast, moderately resistant to fatigue and highly adaptable to training.

Type IIx (fast glycolytic) fibres are pale, wide, rich in glycogen and glycolytic enzymes. They are the fastest and most forceful fibres but fatigue quickly, and they are supplied by large motor neurons. (Type IIb, common in rodents, is barely expressed in human limb muscle.)

Every muscle contains a mixture of types, with proportions set by genetics and training. Endurance training shifts IIx toward IIa and increases mitochondrial density. Resistance training enlarges fibres (hypertrophy), mainly type II. Disuse, denervation and ageing (sarcopenia) cause atrophy.

Length–tension. Active force depends on how much the thick and thin filaments overlap. It peaks at the optimal sarcomere length (≈2.0–2.2 µm in classic studies; slightly longer in humans, whose thin filaments are longer), where every myosin head can reach actin. If the sarcomere is overstretched, overlap falls and so does force. If it is overshortened, thin filaments collide and thick filaments butt against the Z discs, which also reduces force. Passive tension from titin and connective tissue rises steeply when muscle is stretched. In the body, resting muscle length lies close to the optimum. The heart applies the same principle in the Frank–Starling mechanism.

Force–velocity. In concentric contraction, the heavier the load, the more slowly the muscle shortens. At maximal load, velocity falls to zero (isometric force). Eccentric contraction can produce more force than maximal isometric contraction, about 1.5–1.8× in isolated muscle, at lower metabolic cost. It is also the main cause of delayed-onset muscle soreness.

The ATP held in muscle lasts only ≈2–3 s of maximal effort. It is topped up by three systems.

1. Phosphagen system: creatine phosphate + ADP → creatine + ATP, catalysed by creatine kinase. It is very fast and lasts ≈10 s.
2. Anaerobic glycolysis: glucose or glycogen → pyruvate → lactate, giving a net 2 ATP per glucose (3 per glucosyl unit from glycogen). It powers efforts of ≈30 s to 2 min.
3. Oxidative phosphorylation in mitochondria: ≈30–32 ATP per glucose. It also burns fatty acids and dominates prolonged exercise.

After exercise, oxygen consumption stays raised (EPOC, "oxygen debt") to restore creatine phosphate and ATP, reload myoglobin, clear lactate and dissipate heat. Fatigue has several causes. Peripheral causes include accumulation of Pᵢ and H⁺, impaired SR Ca²⁺ release, glycogen depletion and failure of K⁺ handling in the T-tubules. Central causes involve reduced motor drive from the CNS.

Isometric: tension develops but muscle length does not change, as when holding posture or a load still. Isotonic: the muscle changes length under a constant load. It can be concentric (shortening, e.g. biceps lifting a cup) or eccentric (lengthening while active, e.g. quadriceps controlling descent of stairs). Isokinetic: shortening at constant velocity on a dynamometer.

A single twitch has three phases: a latent period (EC coupling), a contraction phase and a relaxation phase. Repeated stimulation produces summation and tetanus. A treppe (staircase) effect, in which a rested muscle gives slightly stronger successive twitches, reflects accumulating Ca²⁺.

Smooth muscle can hold force for long periods at very low ATP cost through dephosphorylated latch bridges.

Cardiac muscle: an L-type Ca²⁺ current during the plateau of the action potential triggers Ca²⁺-induced Ca²⁺ release through RyR2. Contraction is regulated by troponin, as in skeletal muscle. A long refractory period makes tetany impossible. Cells are electrically coupled through gap junctions in intercalated discs, so the myocardium contracts as a functional syncytium.

Smooth muscle has no troponin and no sarcomeres. Ca²⁺ enters from the extracellular fluid and the SR and binds calmodulin. Ca²⁺–calmodulin activates myosin light-chain kinase (MLCK), which phosphorylates myosin and allows cross-bridge cycling. Myosin light-chain phosphatase reverses this and causes relaxation. Thin filaments anchor to dense bodies, so the cell shortens in a corkscrew fashion. Smooth muscle can be activated by autonomic nerves, hormones, stretch or local factors. It contracts slowly but economically, and in single-unit (visceral) smooth muscle, cells coupled by gap junctions act together.

Duchenne muscular dystrophy (DMD) is X-linked recessive and affects ≈1 in 3,500–5,000 male births. It is caused by frameshift (often deletion) mutations in the dystrophin gene at Xp21, one of the largest human genes (≈2.2 Mb, 79 exons). About one-third of cases arise de novo.

Dystrophin links the actin cytoskeleton to the extracellular matrix through the dystroglycan complex. Without it, the sarcolemma tears during contraction. Fibres then necrose and are replaced by fat and fibrous tissue.

Weakness begins at age 2–5 and affects proximal muscles first. Signs include a waddling gait, the Gowers sign (the child "climbs up" their own thighs to stand) and calf pseudohypertrophy. CK is markedly raised (often >10× normal). Most patients lose the ability to walk by about 12 years. Death results from dilated cardiomyopathy or respiratory failure. Glucocorticoids slow progression, and exon-skipping therapies target specific deletions.

Becker muscular dystrophy is caused by in-frame mutations that leave a partly functional dystrophin. Onset is later and progression milder.

Myasthenia gravis is an autoimmune disease in which antibodies against the nicotinic ACh receptor (≈85% of generalised cases, ≈50% of purely ocular cases) or against MuSK or LRP4 reduce the number of functional receptors. This is a type II hypersensitivity reaction. The end-plate potential becomes too small to reach threshold in some fibres.

Patients develop fatigable weakness that worsens with use and through the day. Ptosis and diplopia (ocular muscles) usually appear first, followed by bulbar and proximal limb weakness, and myasthenic crisis can cause respiratory failure. The thymus is abnormal in most patients: hyperplasia in ≈65% and thymoma in ≈10–15%.

Diagnosis uses antibody tests, a decremental response on repetitive nerve stimulation and single-fibre EMG. Treatment includes acetylcholinesterase inhibitors (pyridostigmine), immunosuppression and thymectomy.

Contrast Lambert–Eaton syndrome: antibodies against presynaptic P/Q-type Ca²⁺ channels, often paraneoplastic with small-cell lung cancer, cause weakness that improves with repeated effort, together with hyporeflexia and autonomic symptoms.

Rhabdomyolysis is the breakdown of skeletal muscle with release of its contents into the blood. Causes include crush injury, prolonged immobilisation, extreme exertion, heat stroke, seizures, statins (especially combined with fibrates), alcohol and cocaine, hypokalaemia, malignant hyperthermia and inherited metabolic myopathies (e.g. McArdle disease).

Typical features are myalgia, weakness and dark "tea/cola" urine. CK is greater than 5× the upper limit of normal, often >10,000 U/L. On urine testing, the dipstick is positive for "blood" but microscopy shows no red cells, because the dipstick is detecting myoglobin.

Complications:
- Acute kidney injury: myoglobin causes tubular obstruction and direct haem toxicity.
- Hyperkalaemia, which can cause arrhythmias.
- Hyperphosphataemia and hyperuricaemia.
- Early hypocalcaemia, as Ca²⁺ is deposited in damaged muscle, with rebound hypercalcaemia later.
- Disseminated intravascular coagulation (DIC) and compartment syndrome.

Treatment is early, aggressive IV fluid to maintain a high urine output, correction of electrolytes and treatment of the cause.

Compartment syndrome occurs when pressure rises inside a closed osteofascial compartment until it impairs capillary perfusion. Muscle and nerve become ischaemic, and muscle necrosis can follow within ≈4–6 h. Common causes are tibial and forearm fractures (especially the anterior compartment of the leg), crush injury, reperfusion after ischaemia, tight casts and burns.

The earliest and most reliable signs are pain out of proportion to the injury and pain on passive stretch of the compartment's muscles (e.g. passive toe flexion for the anterior compartment), with paraesthesia. Pallor, pulselessness and paralysis are late signs, and distal pulses are often still present.

The diagnosis is clinical, supported by compartment pressure measurement: absolute pressure above ≈30 mmHg, or a delta pressure (diastolic BP − compartment pressure) below 30 mmHg. Treatment is urgent fasciotomy.

A missed compartment syndrome in the forearm, classically after a supracondylar fracture of the humerus in a child, leads to Volkmann ischaemic contracture.

The supraspinatus tendon is the most commonly torn rotator cuff tendon, typically ≈1 cm from its insertion in a relatively poorly vascularised critical zone. It wears through repeated subacromial impingement under the coraco-acromial arch, and degeneration increases sharply after the age of 40. Acute tears also occur after falls in younger people.

Features include pain over the lateral deltoid at night and when lying on the affected side, a painful arc between ≈60° and 120° of abduction, and weakness of abduction and external rotation.

Each cuff muscle has its own test:
- Supraspinatus: empty-can (Jobe) test, drop-arm test.
- Infraspinatus and teres minor: external rotation lag sign; hornblower's sign for teres minor.
- Subscapularis: lift-off and belly-press tests.

Ultrasound or MRI confirms the diagnosis. Management ranges from physiotherapy to arthroscopic repair.

Medial winging results from paralysis of serratus anterior due to injury of the long thoracic nerve (C5–C7). The nerve runs superficially on the lateral chest wall, where it is vulnerable during axillary dissection or mastectomy, to stab wounds, and in heavy backpack or traction injuries. The medial border and inferior angle lift away from the thorax when the patient pushes against a wall. Overhead abduction beyond 90° is impaired because serratus anterior can no longer upwardly rotate the scapula.

Lateral winging results from weakness of trapezius, after injury to the accessory nerve (CN XI) in the posterior triangle of the neck (e.g. lymph node biopsy). It is accompanied by shoulder droop and weak shrugging. Less commonly, lateral winging follows dorsal scapular nerve palsy affecting the rhomboids.

During single-leg stance, gluteus medius and minimus on the stance side abduct the hip to keep the pelvis level. If these muscles are weak, or their nerve (the superior gluteal nerve, L4–S1) is injured, the pelvis drops on the opposite, unsupported side when the patient stands on the affected leg. This is a positive Trendelenburg sign.

When walking, patients either show a Trendelenburg gait or lurch the trunk toward the affected side (compensated "gluteus medius lurch"). Causes include a misplaced intramuscular injection, hip surgery, L5 radiculopathy, hip osteoarthritis and developmental dysplasia of the hip.

Gluteal intramuscular injections are given into the superolateral quadrant to avoid both the sciatic nerve and the superior gluteal neurovascular bundle.

Indirect inguinal hernias pass through the deep inguinal ring, lateral to the inferior epigastric vessels, and along the inguinal canal, sometimes reaching the scrotum. They follow a patent processus vaginalis and are the most common hernia in both sexes and in children.

Direct inguinal hernias bulge through Hesselbach's (inguinal) triangle, medial to the inferior epigastric vessels, where the transversalis fascia is weak. They are typical of older men. The triangle is bounded by the inferior epigastric vessels, the lateral border of rectus abdominis and the inguinal ligament.

Femoral hernias lie below and lateral to the pubic tubercle, passing through the femoral canal medial to the femoral vein. They are more common in women and have the highest risk of strangulation.

Other types include umbilical, incisional, epigastric and Spigelian (at the semilunar line) hernias. Mnemonic: "MDs don't LIe" — Medial = Direct, Lateral = Indirect.

A strain is a tear of muscle fibres, usually at the myotendinous junction. It typically happens during eccentric contraction of a muscle that crosses two joints (hamstrings, rectus femoris, gastrocnemius medial head, adductor longus).

Strains are graded by severity:
- Grade I: a few fibres torn; pain but strength preserved.
- Grade II: partial tear; weakness, swelling and bruising.
- Grade III: complete rupture, often with a palpable gap.

Hamstring strain (most often the long head of biceps femoris) occurs during the late swing phase of sprinting. Risk factors include a previous strain, fatigue, poor flexibility and strength imbalance. Treatment follows protection, rest, ice, compression and elevation (PRICE), then progressive loading with an emphasis on eccentric strengthening (e.g. Nordic curls). Proximal hamstring avulsions may need surgery.

Both are caused by clostridial zinc-protease neurotoxins that cleave SNARE proteins and so block release of neurotransmitter.

Tetanus (Clostridium tetani, from contaminated wounds): tetanospasmin travels retrogradely up motor axons to the spinal cord. There it cleaves synaptobrevin in inhibitory interneurons (including Renshaw cells), blocking release of glycine and GABA. Unopposed motor firing causes spastic paralysis: trismus ("lockjaw"), risus sardonicus, opisthotonus and painful spasms. It is prevented by tetanus toxoid vaccination and treated with tetanus immunoglobulin, wound debridement, benzodiazepines and airway support.

Botulism (Clostridium botulinum, from food, wounds, or honey in infants): botulinum toxin (type A cleaves SNAP-25; type B cleaves synaptobrevin) acts at peripheral cholinergic terminals and blocks ACh release. The result is a symmetrical descending flaccid paralysis that starts with diplopia, ptosis, dysphagia and dysarthria. Pupils are dilated, the mouth is dry, consciousness and sensation are preserved, and respiratory failure can follow. Infants present as "floppy baby". Treatment is antitoxin and ventilatory support. Therapeutic botulinum toxin is used for dystonia, spasticity, hyperhidrosis, migraine and cosmetic wrinkles.