FRCA Muscles
Smooth muscle
Skeletal
Cardiac
Anatomy
Excitation-Contraction coupling:
Process linking depolarisation of sarcolemma to initiation of myocyte contraction
Muscle
Myocytes: surrounded individually by endomysium
Epimysium covers whole muscle
Sarcoplasmic reticulum: modified ER acting as Ca2+ store
Perimysium covers around 100 myocytes
T-tubule: invaginations of muscle surface membrane (sarcolemma) to relay action potentials deep into myocyte interior
Glycogen stores
many Myofibrils: contractile apparatus arranged in parallel spanning entire length of myocyte, anchored to sarcolemma at either end (to contract and shorten)
long Myofilaments consisting of sarcomere continuous end to end
Sarcomeres: functional unit of skeletal muscle between 2 Z lines
Special features:
Muscle fibre may span entire length of muscle, diameter 50micrometer
Myocytes are multinucleate
Striated (cardiac and skeletal) due to regular sarcomeres
Thin filament (actin)
Thick filament (myosin)
Double helical strand of Fibrous (F) actin consisting of strings of Globular (G) actin subunits. (300-400 actin molecules)
About 7nm diameter
Each G actin can bind to myosin head
Each thin filament has a tropomyosin strand running along groove which blocks active sites of thin filament when muscle is relaxed.
Each tropomyosin has troponin complex bound to it (T, I, C). T binds tropomyosin, I is an intermediate link, C allows Ca2+ to bind and uncover myosin binding site
Titin core to anchor to Z lines.
Myosin (golf-club shaped): tail of 2 intertwined chains and double globular head.
About 15nm diameter
Sarcolemma (cell membrane)
Resting membrane potential -90mV
Synaptic activity at motor end plate causes depolarisation of sarcolemma, triggering action potential along myocyte surface membrane (Endomysium)
T-tubules transmit AP deep into myocyte interior close to SR.
Dihydropyridine receptor (DHPR) senses depolarisation to form a conformation change but allows little Ca2+ to pass. DHPR is a modified subtype of voltage-gated L-type Ca2+ channel.
Ryanodine receptor (RyR) on SR membrane is associated with DHPR. Conformation change of DHPR causes RyR to open and released Ca2+ from SR into sarcoplasm (concentration increases 2000x)
Ca2+ binds to Troponin C, changes conformational change to troponin complex, uncovers myosin binding site and allows actin-myosin interaction.
Myosin heads bind ATP (hydrolysed to ADP and Pi). Energised myosin heads able to bind actin molecules and form cross bridges.
Energised myosin head flexes on its actin binding site to provide power stroke to move actin closer to centre of sarcomere (ADP and Pi dissociate from head)
Fresh ATP binds to myosin head, causing dissociation from actin filament.
Z lines move closer together, width of I band decreases. No change to A band (thick filaments do not shorten)
Proprioception:
Sensory receptors
Muscle spindles:
Encapsulated structure containing 3-12 intracapsular muscle fibres (intrafusal) arranged in parallel with extrafusal contractile fibres (as in skeletal muscle section), such that alteration of length of 1 will affect the other.
Intrafusal fibres have central non-contractile elastic portion and outer contractile ends. They consists of:
Golgi tendon organs:
Stretch receptors located at junction between skeletal muscle and tendon. Arranged in series with extrafusal muscle fibres. Therefore sense muscle tension.
Nuclear bag fibres (nuclei collected in central dilated portion of fibre) sense rate of change
Nuclear chain fibres (nuclei distributed along fibre without dilatation) sense static length
Nerve supply
Afferent:
Type 1α afferent neurons: receive input from both nuclear bag and nuclear chain. Receive information about static intrafusal length and rate of change
Type 2 afferent neurons: receive input from nuclear chain fibres only (only relay information about static length)
Efferent:
ɣ motor neurons innervate contractile outer portions of intrafusal fibres. Each ɣ motor neuron innervates a few muscle spindles
Voluntary contractions involve α-motor and ɣ-motor neuron. Outer part of intrafusal fibre contracts to prevent slackening of spindle despite shortening of extrafusal fibres. Therefore sensitivity of muscle spindles is maintained.
Each innervated by a single type 1b afferent neuron. No motor innervation
Reflex arcs:
Automatic, predictable response to a stimulus. Generally not under voluntary control.
Number of synapses classification
Origin of sensory signal classification
Monosynaptic (knee-jerk)
Polysynaptic (withdrawal on heat)
Striking patellar tendon causes contraction of quadriceps leading to extension of knee.
Sensory: muscle spindles of quadriceps sense stretch
Afferent: type 1a afferent neuron to dorsal root then to ventral horn of spinal cord
Synapse: in ventral horn, the afferent neuron synapses directly with α-motor neuron using glutamate
Efferent: α-motor neuron travels to quadriceps where it innervates several muscle fibres
Effector organ: quadriceps contracts in response to α-motor neuron activity
From ANS (baroreceptor)
From Cranial nerve (gag reflex)
From peripheral sensory afferent neuron (knee-jerk)
Some type 1a afferent neurons branch in spinal cord through interneurons to neurons of antagonistic muscles to relax them (hamstrings) using glycine are neurotransmitter
Descending inputs from brain may modulate intensity of reflexes:
Knee-jerk is lost following repeated rapid patellar strikes.
Jendrassik manoeuvre results in increased ɣ-motor neuron firing, increasing background stretch in spindle
Important distribution of SM
Uterus: primarily composed of SM. Essential for labour and post-partum period
Arteries: vascular SM in tunica media. contraction leads to reduction in luminal radius
Respiratory tract: bronchiolar SM contraction leads to bronchoconstriction
GI tract: coordinated contraction of longitudinal (segmentation) and circular (peristalsis) SM mixes and propels luminal contents
Types of SM
Single-unit:
Found in viscera and blood vessels (except large elastic arteries) as sheets of SM cells forming syncytial units. An ANS neuron innervates single cell within sheet, action potentials rapidly propagate to neighbouring cells through gap junctions leading to synchronous contraction
Multi-unit:
In large elastic artieries, trachea and iris. Not connected by gap junctions. Single ANS may branch to many SM cells in a similar way to motor units in skeletal muscle
Excitation-Contraction coupling
Difference between SM and skeletal muscle:
Size: Skeletal large cylindrical cells that span entire length of muscle. SM are smaller and spindle-shaped cells arranged in sheets
Nuclei: Skeletal muscle cells are multi-nucleate, SM have only 1 nucleus
Sarcomeres: SM not striated; thick and thin filaments not organised into sarcomeres
Troponin: absent in SM
T-tubules: SM does not have T-tubules, but have rudimentary invaginations called caveolae, which increase surface area to volume ratio
SR: The SR (as a store of Ca2+) is poorly developed in SM
Gap junctions: Present on SM but not on skeletal
Slow contractions consume less energy: power of contraction = force x velocity
Latch bridge formation maintains SM tension (if myosin is dephosphorylated whilst still attached to actin, crossbridge remains in place.
Excitation:
Receive both excitatory and inhibitory signals. Net effect determines depolarisation beyond threshold potential.
Multi-unit SM can be stimulated by only nerve impulses but single-unit SM can be stimulated by:
ANS: Single-unit SM is usually innervated by sympathetic AND parasympathetic neurons
Hormones and circulating molecules: e.g. O2, CO2, NO, adrenaline, NorAd, histamine, PG, 5HT
Stretch: Stretch of SM sheet triggers contraction. In arteries this is called myogenic response. In GI tract peristalsis is triggered with stretch
Pacemaker activity: Heart (SA node) and GI tract (interstitial cells of Cajal) have spontaneously depolarising membranes. This occurs 12/min in duodenum, 3/min in colon etc.
Coupling
Lack of T-tubules: action potentials propagated rapidly through gap junctions. Caveolae increase surface area and facilitated Ca2+ entry
Ca2+: lack T-tubules and poorly developed SR mean SM uses other methods to increase Ca2+ influx:
Voltage-gated Ca2+ channels
Ligand-gated Ca2+ channels
Stretch-responsive Ca2+ channels
Calmodulin: Ca2+ binds to calmodulin. This complex then activates SM contraction through:
Myosin light-chain kinase (MLCK): sarcoplasmic enzyme MLCK is activated, phosphorylates myosin light-chains and allows it to form cross-bridges with actin filaments
Caldesmon: Troponin is absent in SM, but replaced by Caldesmon. Ca2+/Calmodulin complex binds to caldesmon to cause conformational change, unblocking myosin binding site and permitting actin-myosin crossbridge cycling
Calponin: this protein inhibits the ATPase activity of myosin head (activated by Ca2+ alone or Ca2+/Calmodulin complex
Contraction:
ATP binds to myosin head, hydrolysis occurs, causing power stroke with release of ADP and Pi, then binding of new ATP molecule.
Slower contraction:
SM action potentials are slower and more prolonged. SR Ca2+ concentrations increase and decrease slowly.
Enzymatic phosphorymation is required before myosin can bind to actin.
Crossbridge cycling is slower than that of skeletal muscle
Muscular anatomy
Broad types of cardiac cells
Atrial and ventricular myocytes (excitable and contractile)
Pacemaker and conducting cells (excitable but non-contractile)
SA and AV nodal cells spontaneously generate action potentials
Purkinje fibres transmit action potentials
Functional syncytium:
Gap junctions permit APs to transmit
Fascia adherens anchor actin filaments within sarcomere to cell membrane
Desmosomes anchor cardiac cells to one another
Similar to Skeletal muscle
Striated appearance due to organised thick and thin filaments.
Sarcotubular system with T-tubules, SR (less developed than skeletal)
Similar to SM
Involuntary control
Gap junctions
Cardiac myocyte action potential
Resting membrane potentials:
SA node: -50mV
Atrial myocyte: -70mV
Purkinje fibre and ventricular myocyte: -90mV
Due to Na/K pumps but in cardiac myocytes, presence of inward-rectifying K channels which are open at negative MPs and close with depolarisation
Action potential is 200-400ms (vs 1-2ms in neuronal cells).
Calcium plays a role in prolonging cardiac AP (no role in nerve AP)
Phase 0 (rapid depolarisation): threshold potential -65mV. Rapid depolarisation to 20mV. Opening fast voltage-gated Na channels
Phase 1 (early rapid depolarisation): Na channels close, fast K channels open towards plateau.
Phase 2 (plateau): L-type Ca channels slowly open, Ca influx. K slow delayed rectifier channels open to let K out.
Phase 3 (repolarisation): gradual inactivation of Ca channels. K channels remain open to allow outflux
Phase 4 (electrical diastole): RMP is maintained due to K efflux through K inward rectifier channels
Absolute refractory period (200ms)
Relative refractory period after that
Pacemaker potential
Spontaneous decay of membrane potential from -60mV to threshold of -40mV (SA node)
Following SA node AP, membrane hyperpolarisation causes opening of hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels. These are permeable to Na and K.
Na influx exceeds K efflux, resulting in slow depolarisation of membrane from -60mV.
When membrane potential reaches -50mV, T-type Ca channels open for Ca influx.
Action of both causes spontaneous migration of membrane potential to threshold of -40mV
Excitation-Contraction coupling
Conduction pathways
Internodal
Middle (Wenckebach pathway)
Posterior (Thorel pathway)
Anterior (Bachmann): also relays to LA via Bachmann bundle
AV node:
Only means to transmit between atria and ventricles. Elsewhere insulated by annulus fibrosus
Bundle of His
Right
Left anterior
Left posterior
Purkinje fibres: rapid conduction through RV and LV to synchronise contractions. fibres terminate just below endocardium
Myocytes:
See functional syncytium
Intracellular Ca2+ concentration increased via Ca-induced Ca release (rather than physical connection between T-tubule, RYR and DHPR)
Atrial myocytes have small invaginations called caveolae which increase surface area. Also contain L-type Ca channels
Ventricular myocytes have T-tubules which contain L-type Ca channels (DHPR). T-tubules conduct APs deep into myocyte interior
Membrane depolarisation causes L-type Ca channels (DHPR) to open.
Ca influx into SR. SR contains RYR, which is opened by Ca influx and then causes SR to release more Ca (Ca-induced Ca release).
Ca binds to TropC and changes conformation to expose myosin binding sites on actin, allow cross-bridge formation.
Termination
Actively removing Ca from cell.
Diastolic relaxation is therefore an ATP dependent process
Plasma membrane Ca-ATPase pump (PMCA): uses ATP to actively remove Ca2+
Na/Ca exchanger (NCX): removes 1 Ca for influx of 3 Na. Driven by low intracellular Ca concentration (maintained by Na/K ATPase pump)
SR/ER Ca-ATPase pump (SERCA): Uses ATP to sequester Ca into SR