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22 Cards in this Set

  • Front
  • Back
Muscle anatomy
Muscle types:
-Striated
--Skeletal
--Cardiac
-Smooth
For striated muscle review:
-organization from muscle fascicle to myofibrils
-structure of the sarcomere
Myofilaments
Myofilaments are critical contractile elements within muscle cells; comprise thin and thick filaments in ordered arrays
The myofilaments in an individual cell are in register, giving rise to striated appearance and influencing excitation-contraction coupling
Thin filaments
G-actin (globular) polymerizes to form F-actin (filamentous)
Tropomyosin helps hold F-actin together
Troponin complex includes:
-Troponin-T: binds to tropomyosin, anchoring the troponin complex
-Troponin-C: binds Ca2+, an essential step in initiating contraction
-Troponin-I: binds to actin, inhibiting actin-myosin interaction

Serum levels of cardiac-specific isoforms of troponin-T and troponin-I: sensitive diagnostics for damage to cardiac muscle
Cardiac isoforms of troponin T and I (cTnT and cTnI) not present in serum from healthy people
Cardiac troponins are preferred markers for detecting myocardial cell injury  
-Rises 2 - 6 hours after injury
-Peak in 12 - 16 hours
-cTnI stays elevated for 5-10 days, cTnT for 5-14 days
Thick filaments
Each myosin II molecule has two polypeptide heavy chains and four light chains (two each of two types)
Myosin light chains (MLC) play structural (may stiffen “neck”) and regulatory roles
Each myosin heavy chain (MHC) globular head - one binding site for ATP and one for actin; head demonstrates ATPase and motor activity
Molecules aggregate tail to tail; globular heads extending so can form cross-bridges to thin filaments
Sarcomere organization and accessory proteins
thin and thick filaments aligned and kept at appropriate distances by accessory proteins
help bind filaments to Z-line or M-line
-thin filaments anchored at z line
-thick filaments anchored at m line
Muscle contraction: sliding filament model overview
Shortening of muscle cell involves rapid contraction cycles that move thin filaments along thick filaments, shortening the sarcomere
Each contraction cycle progresses through several stages
-Attachment (rigor formation)
-Release
-Bending
-Force generation
-Attachment: The Sequel
Note an individual myosin molecule may remain detached from thin filament during a cycle but other heads in same thick filament attach and result in movement of thin filament along thick filament

Since myosin heads in mirror arrangements either side of H band, their movement pulls thin filaments in and shortens sarcomere
I Band and H band narrow; A band maintains its width
Muscle contraction: stage by stage
Stage 1: attachment
When ATP absent myosin head tightly bound to actin
“rigor configuration”
In actively contracting muscle stage 1 ends with binding of ATP to the myosin head

Stage 2: Release
Binding ATP to myosin causes conformational change actin binding site
Reduces affinity myosin head for actin; head uncouples thin filament

Stage 3: Bending
Myosin head further conformational changes, head bends
movement initiated by breakdown ATP to ADP and inorganic phosphate (both remain bound)
Mg++ critical cofactor for ATPase
Linear displacement head relative to thin filament is about 5 nm

Stage 4: Force generation
Myosin head binds weakly to new binding site on neighboring actin molecule if Ca2+ present
Phosphate released and binding affinity between myosin and actin then increases
Force generated by myosin head as returns to unbent position
As myosin head returns forces movement thin filament along thick filament
During “power stroke” ADP lost from myosin head

Stage 5: Attachement - The Sequel
With loss of ADP myosin head again is left attached to the thin filament (rigor configuration) but to a different actin molecule, one closer to the Z line
If ATP still available then cycle can repeat
Key regulators of muscle contraction
ATP
-Immediate pool very limited
-“Resupplied” from creatine phosphate, glycogen, and cellular respiration
Calcium
-Links action potential to myofilament interactions (excitation-contraction coupling)
Other factors/modulators:
-Magnesium (required ATPase activity and other functions)
-Na+ and Na+ channels
-β Adrenergic receptors
Membrane structures and regulating calcium
Regulation of Ca2+ accomplished by transverse tubule system, sarcoplasmic reticulum (muscle-specific form of smooth endoplasmic reticulum- sER), and voltage sensitive, membrane-bound molecules and ion channels

Sarcolemma conducts AP quickly over surface

Transverse tubules (T tubules)
-Close to edges of A-band
-Conduct AP from surface into fiber
-t-tubules continuous with sarcolemma; filled with extracellular fluid
-Transduce the AP to SR

Sarcoplasmic reticulum (SR)
-Expansions of sER lie over each sarcomere
-Closely apposed to T tubules
-Store high concentration of Ca2+
-Release Ca2+ in response to an AP in the t-tubules
-Also remove (re-sequesters) Ca2+ to stop contraction
Excitation-contraction coupling: skeletal vs cardiac
Skeletal:
AP moves down the t-tubule
AP detected by voltage-sensitive DHP (dihydropyridine: L-type calcium) receptors in t-tubule membrane
Conformational change in DHP receptor is communicated to SR membrane and causes opening of ryanodine receptors, which allow Ca ++ out of SR
Activates contraction
Thus ,voltage directly triggers Ca++ release from SR in skeletal muscle
Ca++ release is proportional to membrane voltage

Cardiac:
AP moves down t-tubule
AP detected by DHP receptors that contain a Ca ++ channel and open to allow small amount of extracellular (trigger) Ca ++ into the fiber
Ca ++ binds to ryanodine receptors in SR membrane; open to release a large amount of (activator) Ca++ (CACR)
Thus, calcium, not voltage, is direct trigger of Ca++ release from SR in cardiac muscle
Ca++ release proportional to Ca++ entry during plateau phase of cardiac AP

Recent results suggest cardiac ryanodine receptors may be activated to some extent by conformational changes in dihydropyridine receptors without Ca2+ influx (as in skeletal muscle) - may be a mechanism parallel/ accessory to Ca2+ induced release of Ca2+
With aging, skeletal muscles become more dependent on extracellular Ca2+, much like cardiac muscle cells
Cardiac action potential and calcium influx
In cardiac myocyte electrical activation same mechanism as in nerve cell – depolarization due inflow of sodium ions across cell membrane
Amplitude AP about 100 mV in nerve and muscle
duration of cardiac muscle AP two orders of magnitude longer than in nerve cell or skeletal muscle; duration of cardiac AP about 300 ms
Plateau phase with calcium influx follows depolarization, followed by repolarization via outflow potassium ions
Pumps maintain ion gradients
Structural differences in cardiac vs skeletal muscle
Compared to skeletal, cardiac muscle:
more and larger mitochondria
more glycogen granules
larger and more numerous T tubules (in ventricular muscle)
Contains multicellular “fibers” that are electrically and mechanically coupled
Intercalated disks
Linear cell-to-cell attachments among cardiac muscle cells form “fibers” (variable length); some cardiac muscle cells attach to several others to form branched “fibers”
attachments form via intercalated disks, which appear to cross muscle cells transversely (parallel to striations)
In cardiac muscle AP can propagate from one cell to another in any direction, except at boundary between atria and ventricles where is barrier non-conducting fibrous tissue - requires special conduction system
Get activation wavefronts of complex shapes
Junctions in intercalated disks
Fascia adherens (adhering junctions)
-Major constituent transverse component
-Holds adjacent cells at ends to form “fibers”
-Narrow intercellular space, electron-dense due to extracellular components transmembrane
-Thin filaments terminal sarcomere anchor into fascia adherens
Maculae adherens (desmosomes)
-Help prevent cells from pulling apart under tension
-Found in transverse and lateral components
Gap junctions (communicating junctions)
-Major element lateral component
-Provide ionic continuity among adjacent cardiac muscle cells, so information molecules can pass cell to cell
-Permit cardiac muscle cells to behave as syncytium but with cellular integrity/individuality
Regulation of cardiac contraction
No stimulus from nervous system needed for contraction
Depolarizations arise spontaneously and rhythmically in cells of the pacemaker - sinoatrial (S-A) node
Initiates impulse that spreads along muscle cells of atrium and via tracts of modified cardiac muscle cells
Latter convey impulse 4X faster than cardiac muscle fibers and convey impulse across fibrous skeleton of heart and thus from right atrium to other chambers
Characteristics of cells of SA node
Cells in SA node smaller than other cardiac muscle cells, have fewer and poorly organized myofilaments; lack intercalated disks but have some intercellular junctions
Cells of SA node exhibit slow depolarization in late stage of each AP; causes them to spontaneously reach membrane potential at which new AP is generated
Not all nodal cells depolarize at same rate; ones that reach threshold first (pacemaker cells) rapidly bring others to threshold
Isolated nodal cells depolarize 80-100 times per minute but factors that alter the resting potential or rate of depolarization affect the heart rate
Characteristics of cells of AV node
AV node located right atrium, near lower part interatrial septum
Cells in AV node similar to those in SA node - smaller, fewer and poorly organized myofilaments, no intercalated disks
Cells of AV node exhibit slow depolarization in late stage each AP but depolarization in AV node slower than in SA, so AV normally triggered by impulse coming from SA, not intrinsically
If SA node damaged, AV node takes over (less effectively)
AV node normally slows conduction of impulse as it travels from atria to ventricles, causes approximately 0.1 second delay between contraction of upper and lower chambers - permits atria to complete contraction and empty blood into ventricles before ventricles contract
Bundle fibers and Purkinje cells
As progress from AV node, cells become bigger and take on appearance of Purkinje cells - bigger than cardiac muscle cells, contain large amounts glycogen, few myofilaments (only in periphery of cell)
Intercalated disks relatively infrequent in Purkinje cells, but frequent gap junctions
Conduction along Purkinje cells speeded up by:
-Large size
-Abundant glycogen
-Absence of T tubules
-Frequent gap junctions
-Insulation from surrounding myocardium by sheath of connective tissue

Transitional cells (terminal Purkinje fibers) that penetrate ~ 1/3 of the way into the myocardium and end on ordinary cardiac muscle cells
Propagation within cardiac muscle
From inner side ventricular wall, many activation sites cause formation of wavefront that propagates through ventricular mass toward outer wall by cell-to-cell activation
After each ventricular muscle region has depolarized, repolarization occurs
Duration of AP is shorter near epicardium; termination of activity appears as if it were propagating from epicardium toward the endocardium
Neural regulation of heart contraction
Autonomic fibers regulate, but do not initiate, contraction of cardiac muscle
Parasympathetic fibers from CN X synapse on postsynaptic neurons in heart, which terminate primarily in the SA and AV nodes (also extend into coronary arteries)
Sympathetic fibers from levels T1 to T6 innervate the SA and AV node, extend into myocardium, and also through epicardium to coronary arteries
Autonomic effects on heart contraction
ACh from parasympathetic fibers decreases heart rate (bradycardia) by slowing rate of depolarization of nodal cells; also reduces force of contraction through stimulation muscarinic receptors on nodal cells and myocytes, and constricts coronary arteries
NE released by sympathetic fibers leads to increased heart rate (tachycardia) by increasing rate of depolarization nodal cells and increases force of contraction via activation of beta receptors on nodal cells and cardiac myocytes; also produces dilation of coronary arteries by inhibiting their constriction
Hormonal and drug effects on heart contraction
Hormones secreted by adrenal medulla influence rate/force of contraction - activation of adrenergic receptors (primarily β1) by epinephrine or norepinephrine
Calcium, thyroid hormones, caffeine and cardiac glycosides (digoxin) increase intracellular calcium in myocytes
Adrenergic receptor antagonists (e.g. –olol drugs) and calcium channel blockers decrease rate/force