Muscle, NMJ & Vasculitis

Skeletal muscle: sarcomere and excitation–contraction coupling

Sarcomere. The contractile unit runs from Z line to Z line. Thin actin filaments, which carry troponin and tropomyosin, anchor at the Z lines; thick myosin filaments occupy the center. Filaments slide past each other without changing length, so during contraction the A band (the length of the thick myosin filaments) stays constant, while the I band (thin actin only) and the H band (myosin only) shorten as the Z lines draw together.

The A band is Always the same length; the I and H bands shrink (actIn is thIn).

Excitation–contraction coupling. Depolarization travels down the T-tubule and activates the voltage-sensing dihydropyridine (DHP) receptor, which is mechanically coupled to the ryanodine receptor of the sarcoplasmic reticulum (SR). Ca²⁺ binds troponin C, tropomyosin shifts off actin's myosin-binding sites, and cross-bridges cycle. The power stroke requires ATP: ATP binding detaches myosin from actin, and its hydrolysis re-cocks the head. SERCA pumps Ca²⁺ back into the SR to relax the muscle.

Correlations. Cardiac muscle lacks the mechanical link: Ca²⁺ entering through L-type channels triggers Ca²⁺-induced Ca²⁺ release. With no ATP, myosin cannot detach from actin, which explains rigor mortis. Mutations in the skeletal ryanodine receptor (RYR1) cause malignant hyperthermia, uncontrolled SR Ca²⁺ release triggered by volatile anesthetics or succinylcholine and treated with dantrolene.

Muscular dystrophies

Duchenne muscular dystrophy. X-linked recessive, caused by a frameshift or nonsense mutation (usually a deletion) in the dystrophin (DMD) gene, the largest human gene, so new mutations are common. Dystrophin normally anchors the actin cytoskeleton to the sarcolemma and, through the dystroglycan complex, to the extracellular matrix; without it, fibers tear with contraction and are replaced by fat and fibrous tissue. Onset is before age 5 with proximal weakness, a Gowers sign (the child "walks" the hands up the legs to stand), calf pseudohypertrophy from fibrofatty replacement, and a very high CK. Dilated cardiomyopathy causes death, along with respiratory failure.

Deleted Dystrophin = Duchenne: a frameshift truncates the protein, so none is made.

Becker muscular dystrophy. Also X-linked, but the mutation is non-frameshift (in-frame), so partially functional dystrophin remains. Onset is later (adolescence to adulthood), progression is milder, and survival is longer.

Myotonic dystrophy type 1. Autosomal dominant CTG trinucleotide repeat expansion in DMPK; like other repeat disorders it shows anticipation. Features are myotonia (delayed release of a grip or handshake), muscle wasting, early cataracts, frontal balding, testicular atrophy, and cardiac arrhythmias.

CTG: Cataracts, Toupee (frontal balding), Gonadal atrophy.

Neuromuscular junction: myasthenia gravis vs Lambert-Eaton

Myasthenia gravis. Autoantibodies (type II hypersensitivity) against the postsynaptic nicotinic ACh receptor reduce the number of working receptors, so transmission fails with repeated firing. Ptosis, diplopia, and proximal or bulbar weakness worsen with use and through the day. It is associated with thymoma or thymic hyperplasia (thymectomy can help). Symptoms improve with AChE inhibitors: edrophonium (short-acting, diagnostic) and pyridostigmine (maintenance).

Lambert-Eaton myasthenic syndrome. Antibodies against presynaptic voltage-gated calcium channels reduce ACh release. Proximal (especially leg) weakness improves with repeated use as Ca²⁺ accumulates in the nerve terminal (incremental response), with hyporeflexia and autonomic signs such as dry mouth. It is paraneoplastic to small cell lung cancer and responds poorly to AChE inhibitors.

Large- and medium-vessel vasculitis

Giant cell (temporal) arteritis. Granulomatous inflammation of carotid branches in women over 50: unilateral headache, jaw claudication, and vision loss from ophthalmic artery involvement, with a high ESR and often polymyalgia rheumatica (shoulder and hip girdle pain and stiffness).

Start high-dose steroids immediately to save vision and biopsy afterward; skip lesions mean a negative biopsy does not exclude disease.

Takayasu arteritis ("pulseless disease"). Granulomatous thickening of the aortic arch and its branches in Asian women under 40, producing weak upper-limb pulses.

Polyarteritis nodosa. A medium-vessel vasculitis linked to hepatitis B. Transmural fibrinoid necrosis of renal and visceral arteries yields lesions of different ages and string-of-pearls microaneurysms. It spares the lungs and is not ANCA-associated. Features are renal failure, GI pain, skin nodules, and mononeuritis multiplex.

Kawasaki disease. A medium-vessel vasculitis of children under 5 (often Asian): fever over 5 days plus CRASH (Conjunctivitis, Rash, Adenopathy, Strawberry tongue, Hand-foot erythema and desquamation). Coronary artery aneurysms can cause myocardial infarction, so echocardiography follows diagnosis. Treat with IVIG and aspirin, a rare pediatric indication for aspirin despite Reye syndrome risk.

Buerger disease (thromboangiitis obliterans). A segmental thrombosing vasculitis of small and medium extremity vessels in young heavy smokers, usually men: intermittent claudication, Raynaud phenomenon, and ulceration or gangrene of the fingers and toes. The treatment is complete smoking cessation.

Small-vessel vasculitis and the vessel-size map

Granulomatosis with polyangiitis (Wegener). A c-ANCA (anti-PR3) vasculitis with necrotizing granulomas and a triad: upper respiratory (sinusitis, saddle-nose deformity), lower respiratory (lung nodules, hemoptysis), and renal (pauci-immune crescentic glomerulonephritis).

Other small-vessel diseases. Microscopic polyangiitis and Churg-Strauss (eosinophilic granulomatosis with polyangiitis) are p-ANCA (anti-MPO); only Churg-Strauss forms granulomas. IgA vasculitis (Henoch-Schönlein purpura) is immune-complex mediated rather than ANCA-associated and typically follows an upper respiratory infection in children.