Smooth Muscle Physiology & Muscle Fiber Types

Smooth Muscle Contraction: The Calmodulin Switch

Raising cytosolic calcium. Ca²⁺ enters through L-type voltage-gated channels when the membrane depolarizes and through receptor-operated (ligand-gated) channels. Gq-coupled receptors (α1, M3, AT1, endothelin-A, H1, V1) activate phospholipase C, which generates IP₃; IP₃ opens IP₃ receptors on the sarcoplasmic reticulum (SR) and releases stored Ca²⁺ even without depolarization. Contraction driven by a hormone or drug rather than an action potential is called pharmacomechanical coupling.

Calmodulin, not troponin. Four Ca²⁺ ions bind calmodulin. The Ca²⁺–calmodulin complex activates myosin light-chain kinase (MLCK), which phosphorylates the regulatory light chain of myosin II and switches on cross-bridge cycling. Regulation is therefore thick-filament (myosin-linked). Smooth muscle has no troponin and no sarcomeres; actin filaments anchor to dense bodies, which are pulled together as the cell shortens.

Relaxation and the Drugs That Exploit It

Turning contraction off. Myosin light-chain phosphatase (MLCP) removes the phosphate, while SERCA, the plasma-membrane Ca²⁺-ATPase, and Na⁺/Ca²⁺ exchange lower cytosolic Ca²⁺. β2 agonists raise cAMP, and protein kinase A phosphorylates MLCK to blunt its activity, producing bronchodilation and tocolysis. Rho kinase does the opposite: it inhibits MLCP, sensitizing the contractile machinery to Ca²⁺ and contributing to vasospasm.

Nitric oxide–cGMP pathway. Endothelial NO synthase (Ca²⁺–calmodulin-dependent, stimulated by acetylcholine, bradykinin, and shear stress) makes NO from L-arginine. NO diffuses into smooth muscle and activates soluble guanylyl cyclase, raising cGMP; protein kinase G then activates MLCP and lowers Ca²⁺. Nitrates donate NO and dilate veins more than arteries, lowering preload. Natriuretic peptides raise cGMP through a membrane-bound guanylyl cyclase instead.

PDE5 inhibitors. Sildenafil and tadalafil block PDE5 breakdown of cGMP in the corpus cavernosum and pulmonary arteries, treating erectile dysfunction and pulmonary hypertension; tadalafil also treats BPH. Sildenafil weakly inhibits retinal PDE6, causing blue-tinged vision (cyanopsia).

Nitrates plus a PDE5 inhibitor are contraindicated: one increases cGMP production and the other blocks its breakdown, so cGMP soars and blood pressure crashes.

Tone and Organization

Latch state. When the light chain is dephosphorylated while myosin is still attached to actin, these latch bridges detach very slowly. Force is maintained with minimal cycling and ATP use, which suits sphincters and resting vascular tone.

Single-unit (visceral) smooth muscle. Cells are electrically coupled by gap junctions (connexins) into a functional syncytium and driven by pacemaker slow waves. Examples are the gut (paced by interstitial cells of Cajal), uterus, bladder, ureter, and small vessels. Near term, estrogen increases myometrial gap junctions (connexin 43) and oxytocin receptors so the uterus contracts as one unit, whereas progesterone keeps it quiet during pregnancy.

Multi-unit smooth muscle. Individually innervated fibers allow fine, graded control: iris, ciliary muscle, arrector pili, and vas deferens.

Excitation–Contraction Coupling Compared

Skeletal muscle. The T-tubule action potential shifts the dihydropyridine (DHP) receptor, an L-type channel (Ca_v1.1) that acts as a voltage sensor physically linked to RyR1 on the SR at the triad. SR Ca²⁺ floods out without any need for Ca²⁺ entry, binds troponin C, and tropomyosin moves off the myosin-binding sites on actin. Calsequestrin stores Ca²⁺ inside the SR.

RyR1 mutations plus volatile anesthetics or succinylcholine cause malignant hyperthermia (rigidity, hypercarbia, hyperthermia); dantrolene blocks RyR1.

Cardiac muscle. Ca²⁺ entering through L-type channels (Ca_v1.2) during the plateau triggers RyR2 at the dyad: calcium-induced calcium release. Contractility therefore depends on extracellular Ca²⁺, and verapamil and diltiazem are negative inotropes. SERCA2a, regulated by phospholamban, and the Na⁺/Ca²⁺ exchanger remove Ca²⁺ for relaxation.

Skeletal Fiber Types, Recruitment, and Biopsy Patterns

Fiber types. Type 1 (slow oxidative, red) fibers are rich in mitochondria, myoglobin, and capillaries, resist fatigue, and dominate postural muscles such as the soleus and paraspinals. Type 2 (fast glycolytic, white) fibers rely on fast myosin ATPase, glycogen stores, and anaerobic glycolysis for brief, powerful bursts but fatigue quickly; type 2a fibers are intermediate. The motor neuron determines a fiber's type, and all fibers of one motor unit share it. Mnemonic: "one slow red ox."

Size principle (Henneman). Small, low-threshold motor neurons supplying type 1 fibers are recruited first; large type 2 units join only as force demands rise, and faster firing (summation toward tetanus) adds still more force. Endurance training adds mitochondria and capillaries, while resistance training hypertrophies type 2 fibers by adding myofibrils.

Denervation. Denervated fibers fire spontaneously, producing fibrillation potentials and positive sharp waves on EMG. Surviving axons sprout and reinnervate neighboring fibers, which adopt the type of their new neuron, so the normal checkerboard mosaic becomes fiber-type grouping; if that neuron is later lost, grouped atrophy follows. This pattern is typical of motor neuron disease such as ALS.

Disuse and steroids. Disuse, glucocorticoids, and cachexia cause selective type 2 fiber atrophy. Steroid myopathy produces proximal weakness with a normal CK. Other biopsy patterns point elsewhere: perifascicular atrophy suggests dermatomyositis, and ragged-red fibers suggest mitochondrial myopathy.