Download 08 General principles of skeletal, cardiac, and smooth muscles II

08 General principles of skeletal, cardiac, and smooth muscles II

skeletal and cardiac muscle share many properties, they also feature some key differences
o commonalities due to shared requirement of rapid, strong contraction
o differences arise because of the differing manner in which these contractions occur
Contractile Machinery
 As in skeletal muscle cells, the contractile machinery of cardiac muscle is organized into sarcomeres, which
contain essentially the same proteins (actin, myosin, troponin, tropomyosin, etc…), albeit with different
isoforms
o Thus, cardiac muscle, like skeletal muscle, is striated
 Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are isoforms unique to heart muscle
o Both appear in the circulation within 3 hours of acute myocardial infarction
o Their appearance in blood indicates ischemia-induced necrosis and loss of myocyte integrity
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The major structural difference is cardiac muscle cells do not extend the length of the heart
o They are short, have one nucleus, branch extensively, and are connected to neighbors by an
intercalated disc
o all cardiac muscle cells are connected to each other, allows the heart to function as a single unit
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The sarcoplasmic reticulum in heart myocytes is more sparse than in skeletal muscle
T tubules are larger in cardiac muscle but have less predictable connections to the SR
o Cardiac muscle does not have precisely arranged triads, but has diads, where a single pod-like ending
of the SR contacts the T tubule
Excitation-Contraction Coupling
 action potential arrives at a diad, activates L-type Ca++ channels in the T tubule membrane (the sarcolemma),
creating a calcium influx (a scenario very similar to skeletal muscle)
o at this point, two major differences are observed in heart vs. skeletal muscle
 Calcium Channel Interactions
 no physical interaction between the L-type Ca++ channels of the T-tubule, and the
(calcium-induced) Ca++-release channels of the SR
 Instead of mechanical activation, it is the calcium influx (trigger influx) into the
cytosol (through L-type channels) that causes release of calcium from the SR into the
cytosol (through Ca++-release channels)
 The extracellular calcium binds the Ca++-release channels to cause activation
 Calcium Requirement
 the L-type Ca+ channels dont permit sufficient influx of Ca to cause muscle contraction
 However, this extracellular influx of calcium is absolutely required in order to
stimulate the release of intracellular calcium stores (from the SR) into the cytosol
 In the end, both intracellular and extracellular sources of calcium contribute to
contractions, but the former provides a much greater source (~90% and ~10%,
respectively)
Control
 Despite the lack of a mechanical link between L-type Ca++ channels of the T-tubule, and Ca++-release
channels of the SR, it is believed that only one L-type Ca++ channel controls one Ca++-release channel
o This 1:1 relationship is to improve the control of Ca release into the cytosol of cardiac myocytes
 In skeletal muscle, an action potential always results in maximal release of calcium from the
SR, but in cardiac muscle, the amount of calcium released by an action potential can be
modified by the ANS
Contraction
 Compared to skeletal muscle, cardiac muscle fibers have 2 main differences when they contract
1. all muscle cells of the heart contract in unison
a. when specialized cells generate action potential, it spreads rapidly throughout the entire heart
i. due to intercalated discs (which connect all muscles) features gap junctions where
ions rapidly pass and propagate action potential
1. all muscles depolarize at nearly the same time creating the heartbeat
2. cardiac muscle cells exhibit a different action potential
a. Longer Absolute Refractory Period
i. much longer than in skeletal muscle cells
1. because the Ca++-release channels of the SR are slow to close, or the SR is
slow to resequester calcium
2. the longer-lasting presence of calcium in the cytosol maintains the
depolarization of the action potential and creates a plateas
3. Tetanus
a. short absolute refractory period in skeletal muscle permits
individual twitches to summate, producing a sustained contraction
known as tetanus
b. In heart, tetanus would be lethal, as the rhythmic pumping of blood
would stop and is why we have the longer absolute refractory period
4. Sustained Contraction
a. Because of the longer absolute refractory period, single
contractions last longer in cardiac contractile cells than in skeletal
b. This forces the ventricles to empty of blood as much as possible
Control
 skeletal is under voluntary (somatic) control, cardiac is under involuntary (autonomic) control
o First, the heart has autorhythmicity (beat on its own) due to intrinsic cardiac conduction system
o Second, the cardiac conduction system is subject to control by the autonomic nervous system
 In skeletal muscle, strength of contraction can be increased by recruiting additional motor units and/or
increasing the firing rate of fibers, thus inducing tetanus
 In the heart, all muscle cells beat as one, thus when attempting to increase strength of contraction
(contractility), more cells cannot be recruited and tetanus would be lethal
o The heart increases contractility (and heart rate) by increasing intracellular calcium concentration
without inducing tetanus
o result from hormonal signals
o In response to the need for greater cardiac output, the sympathetic nervous system has two effects
1. More norepinephrine (acting as neurotransmitter) released at the nerve terminal
2. More epinephrine (acting as hormone) secreted into blood by the medulla of the adrenal glands, and
travels to cardiac muscle cells
o Protein Phosphorylation
o Epinephrine and norepinephrine both bind β1 adrenergic receptors on the cell membrane
(sarcolemma) and activate the cAMP 2nd messenger system
o Ultimately, protein kinase A is activated and phosphorylates two key targets
 L-type Ca++ channels: phosphorylated channels are preferentially open, thus increasing
calcium influx and causes stronger contraction
 The SERCA pump
 disinhibited by activation of phospholamban, allowing the pump to cycle faster,
which achieves two outcomes
o Intracellular Ca++ concentration drops to resting levels more quickly
 The heartbeat happens more quickly
o More Ca++ is resequestered to the SR
 The next heartbeat is stronger
o Unlike skeletal muscle, cardiac muscle does not contain satellite cells
o damaged cardiac muscle is repaired only by fibrosis
o Fibrosis greatly reduces the compliance of the heart, and thus its ability to properly contract
Smooth muscle
 found throughout the body, in three general locations
1. In the walls of hollow organs
a. Stomach and intestines, blood vessels, lung airways, ducts of reproductive tract, bladder and
ureters
2. In the eye
3. In the skin, associated with hairs
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Skeletal and cardiac muscle are both designed to contract rapidly, thus facilitating locomotion and sustaining
cardiac output, respectively
o performs tasks on a less urgent time scale
o in many organs (blood vessels) remains contracted for extended periods, and consumes little energy
In all three muscle types, fiber direction dictates the effect of muscle contraction
o arrangement of cardiac muscle fibers is unique to demands of the heart, and cant be easily categorized
o skeletal and smooth muscle fibers are essentially arranged in two ways—linearly and circularly
 linearly: contraction lessens the linear distance between two points
 This arrangement predominates in skeletal, but is also regularly noted in smooth
 Longitudinal smooth muscle of GI tract scrunches the gut tube in order to propel a
bolus of food
 Arrector pili muscles of skin pull on hairs elevating them and creating goose bumps

Circular: contraction results in constriction of a passageway, while relaxation results in
dilation of the passageway
o predominates in smooth muscle but sometimes noted in skeletal
 Orbicularis ori around the mouth, and orbicularis oculi around the eye, are
essentially dilators/sphincters that guard the aforementioned openings

Smooth muscle occurs as bundles, or sheets of elongated fusiform cells with tapered ends
o Smooth muscle is not striated, hence the term smooth
o Individual cells possess a single, centrally-located nucleus

As in skeletal and cardiac, actin and myosin are the contractile proteins of smooth muscle
o actin and myosin, with other proteins, are organized into thick and thin filaments
 thick filaments are composed of bundled myosin proteins
 in smooth muscle, the thick filament is side-polar, as opposed to bi-polar
 thin filaments contain actin and the smooth muscle isoform of tropomyosin, but not troponin
 instead proteins caldesmon and calponin play a minor regulatory role in contraction
o In a smooth muscle cell, there are no Z-discs, no sarcomeres, and no striations, but there is comparable—
though less formally organized—arrangement of the filaments
o thin filaments are anchored to α-actinin-rich dense bodies, which act as type of Z-disc
o Thick filaments are located in-between the thin filaments: when the thick filaments are activated, they pull
on the thin filaments (as in skeletal and cardiac muscle)
o Finally, the contractile units align roughly with the long axis of the cell
o
o
Dense plaques similar to dense bodies, but are located on the periphery of the cell, where they are linked
with counterparts on adjacent cells
 tension development is evenly distributed across entire sheets of smooth muscle, and coordinated
contraction occurs
 Note that dense bodies are connected to dense plaques by intermediate filaments of the
cytoskeleton, such as desmin and vimentin
Recall that the sarcoplasmic reticulum (SR) is common to fibers of all three muscle types, and that T tubules
are found only in skeletal and cardiac muscle
o Least organized in smooth muscle
o Caveolus: The equivalent of the T tubule in smooth muscle
Excitation-Contraction Coupling
o As in skeletal and cardiac muscle, cross-bridge cycling begins with increased cytosolic calcium levels
o the source for calcium is both extracellular, and intracellular (the sarcoplasmic reticulum in all cases)
o unlike skeletal muscle (but similar to cardiac muscle) the build-up of calcium in smooth muscle may be
initiated by action potentials, or hormonal signals
Varicosities
o Autonomic nerve fibers do not form single, precise neuromuscular junctions with smooth muscle cells
o Instead, a nerve fiber has thousands of periodic swellings known as varicosities—filled with
neurotransmitter-containing vesicles—which contact muscle cells
o Where the varicosity contacts the myocyte is a chemical synapse, similar to a neuromuscular junction
Depolarizating Stimulus
 As in skeletal and cardiac muscle, depolarization of smooth muscle triggers influx of calcium through L-type
Ca++ channels in the caveolae (of the sarcolemma)
 In addition, the calcium entering the cell also stimulates release of more calcium by the sarcoplasmic
reticulum via SR Ca++-induced Ca++ release channels
Hormonal Stimulus
o important mechanism for calcium release from the SR of smooth muscle is the IP3 pathway
o In this case, the binding of a hormone (or other ligand), causes a chain of reactions ultimately producing IP 3—
which diffuses from the cell membrane to Ca++ channels of the SR, inducing them to open
o contraction occurs without depolarization of the cell membrane (both skeletal and cardiac first require
an action potential before any calcium release)
Action Potential vs Hormone
o stimulation by action potential is more common in smooth muscle of gut and others that function as a unit
o in these organs (much like heart) a single action potential can activate thousands of cells
o Stimulation by hormones is more prevalent in smooth muscle of the vasculature and the airways
o Here, very localized control—by maybe only a handful of cells—is often required
In striated muscle, myosin ATPase (head that binds ATP) activity is intrinsic (turn itself on), and is very high
o the regulatory step in cross-bridge formation is binding of calcium to troponin, which pulls tropomyosin
away from myosin binding sites on actin
o In striated muscle, cross-bridge formation is said to be thin filament-regulated
In Smooth Muscle myosin ATPase activity is not intrinsic, and must be initiated by regulatory mechanisms
o cross-bridge formation is thick filament-regulated
 Note that thick filament regulation is due to the expression of a distinct myosin isoform in smooth
muscle
Steps
 Four calcium ions bind calmodulin—a cytosolic protein which similar to troponin in form and function—
and induce a conformational change, such that calmodulin activates myosin light chain kinase (MLCK)
 Activated MLCK phosphorylates the regulatory light chain of myosin with one ATP, which serves only to
activate the myosin ATPase (an additional ATP is still required for each powerstroke)
 The activated ATPase can now bind actin and (in presence of ATP) initiate the power stroke
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Termination
In smooth muscle, an increase in Ca results in the phosphorylation (activation) of myosin
Since myosin ATPase remains active while phosphorylated, a decrease in cytosolic calcium does not stop crossbridge cycling—only dephosphorylation of myosin by myosin phosphatase may terminate contraction
(however, calcium must still be cleared from the cytosol)
o Myosin phosphatase is constitutively active, so when calcium concentrations decrease, MLCK activity
decreases, and myosin phosphatase activity predominates
Caldesmon and Calponin
 proteins associated with the thin filament—play a role in the regulation of cross-bridge formation
o At low calcium levels, these are believed to block myosin binding sites on actin
Shortening
 One key difference is the side-polar arrangement of the thick filaments
o This is to permit a greater shortening of contractile units, allowing cells overall greater shortening
Speed
 speed is not essential in contraction of smooth muscle and frequency of cross-bridge cycling is less in smooth
 the force generation in smooth muscle may be greater than in striated muscle
Types of Smooth Muscle
 goal is controlling passage through hollow organs (blood in arteries, air in bronchial tree, food in the gut, etc…)
o accomplished by varying state of contraction in walls of the organs; organs are contract most of the
time, then relax; some relax most of time, then contract, some have predictable waves of contraction
o
o
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Phasic smooth muscle: contracts in waves, or phases (important for peristalsis in the intestines)
 isimilar to cardiac muscle, that many cells contract in unison to achieve a single goal
 similarity with cardiac muscle is that phasic smooth muscle is autorhythmic, with certain
cells generating an action potential that spreads rapidly, depolarizing all cells in proximity
Tonic smooth muscle: maintains tonic (steady) contractions (this is important in sphincter muscle)
 similar to skeletal, individual contractions may be summated
Phasic and tonic subsets of smooth muscle behave because of electrical arrangement between individual cells
o Phasic smooth muscle is also known as single-unit (unitary) smooth muscle
 Coupled by gap junctions
 Single action potential propagates through all coupled cells and contract as unit
 Key in GI, bladder, uterus
o Tonic smooth muscle is also known as multi-unit smooth muscle
 a single cell is innervated by single neuron, and there is little electrical coupling between cells
 each cell (or small group of cells) behaves as its own unit (thus the term multi-unit)
 key in organs which require a high degree of control (i.e., iris and lens muscles)
In practice, most organs contain a blend of smooth muscle, with predominance of one or the other
I.e., smooth muscle of intestinal wall is primarily phasic, ideal for creating peristaltic waves of contraction
Latch State
 Tonic smooth muscle must often maintain high force for long periods, a situation that would be untenable (due to
fatigue), if it consumed ATP at rates similar to striated muscle
o smooth muscle consumes ~300X less ATP than skeletal muscle would, to maintain the same force
 The key to this phenomenon is the latch state
 At the conclusion of an extracellular signal (action potential or hormone), Ca concentration drops
o In tonic/multi-unit smooth muscle, intracellular Ca concentration falls less drastically than phasic
o myosin phosphorylation (by MLCK) still occurs, but myosin de-phosphorylation (by MP) predominates
 With de-phosphorylation of myosin regulatory light chain predominant in low calcium
concentrations, many cross-bridges are terminating
 However, an important property of tonic smooth muscle is that actin-myosin interactions
persist for some time following de-phosphorylation of myosin
o During this time, tension is created without the use of energy (ATP)
Regeneration
 Unlike skeletal and cardiac muscle, smooth muscle is capable of hypertrophy, and hyperplasia
o an organ, such as the uterus, grows by the addition of new myocytes, and the enlargement of existing ones
o In addition, injured smooth regenerates well due to its mitotic capabilities
Length Adaptation
 Smooth muscle must maintain full contractility even when stretched well beyond its resting length
o For example, bladder volume can increase from 6 mL to 500 mL
 Unlike skeletal and heart, smooth muscle can accommodate for situations with length adaptation
 The length-tension curve of smooth muscle displays an ability to shift leftward or rightward as
a means of maintaining maximal tension at non-optimal lengths
 When stretched, smooth muscle cells replicate contractile units and insert them in series
with existing units
 Upon return to normal length, units are removed