Muscle II Flashcards
Smooth muscle regulation
Has NO troponin
Calcium is still the key regulatory molecule
Smooth muscle contraction cycle.
Increased Ca in the smooth muscle cell binds calmodulin. Ca-calmodulin binds to CaM kinase and activates it, so one of the light chains of myosin head is phosphorylated.
Phoshorylated myosin then can bind actin… force generated.
Process is much SLOWER than skeletal and cardiac muscle.
Slow steps in smooth muscle contraction?
Phosphorylation of myosin is slow and rate of ATP hydrolysis (cross-bridge turnover) is slow.
Can take a second to generate full force.
How do you remove calcium?
Ca pumps and Na-Ca exchangers in the sarcolemma.
Removal of Ca leads to inactivation of the kinase, so myosin is then dephosphorylated by a phosphatase.
Bound and locked in contracted state?
Smooth m can remain in state where mysoin and actin are bound and locked in a contracted state without consuming ATP.
Dystrophin
Associated with Duchenen Muscular dystrophy.
Large, filamentous protein that is associated with both actin (NOT ACTIN IN THIN FILAMENT< but an actin at the surface below the plasma mem) and the surface of the mem.
Part of a complex that spans the PM. Binds ECM mlcs like laminin.
So dystrophin links the cytoskeleton with the ECM.
Titin, nebulin, alpha-actinin
Structural proteins that maintain highly ordered sarcomeres.
Titin: enormous. Links myosin thick filaments to the Z line (those are the far side lines). Titin is extensible. It keeps the myosin thick filaments centered in a sarcomere.
Nebulin: large. Associated with thin actin fil. Keeps them organized. Contribute to passive tension in muscle. (kind of wraps around them).
Alpha-actinin: at the z-line. Cross-links actin filaments. Necessary for attaching actin to Z line.
Sudden cardiac death
About half in young athletes due to familial hypertrophic cardiomyopathy.
LV wall is thick.
Mutation in cardiac myosin heavy chain (head region that interacts with myosin and in 2 regions of head, one that binds actin and one that binds ATP).
Can also be due to troponin mutations.
Single AA mutations in regulatory regions! Bad!
How does this whole contraction thing start?
Action potential in motor axon causes release of neurotransmitter (acetylcholine (AcH)).
Ach diffused across synaptic clef, binds AChR in the post-synaptic membrane.
AChR is an ion channel that opens and causes DEPOLARIZATION.
This causes Na channels to open, action potential initiates.
Action potential….
AP propagates in both directions (electrical signal is faster than contraction, makes sense because you want contraction all at once uniformly).
In cardiac and smooth muscle, Cav are important and open.
Skeletal muscle specifically
But for skeletal muscle, you have AP transmitted to interior via the transverse-tubule (t-tubule) membrane. AP goes towards tendons and into t-tubules.
Ca is then triggered for release from the sarcoplasmic reticulum.
Depolarization in t-tubule membrane does not go directly to the SR. There is no electrical continuity b/w SR and t-system.
Get excitation-contraction coupling.
E-C coupling
Myofilaments are bundled into myofibrils, which are wrapped in their own SR.
End of SR at contact with t-tubule is called termina cisterna, has calsequestrin (which can bind 50 Ca).
Where SR and t-tubule meet you get dark staining, and it’s called the triad.
Proteins that connect the t-tubule and SR
DHPR: complex of several membrane proteins in the t-tubule membrane. One subunit is a Cav.
RyR: in SR membrane. Ca release channel.
Depolarization causes conformational change in the DHP receptor, that in turn causes the Ca release channel to open. Ca flows out of the SR.
Malignant hyperthermia
Mutation in proteins at t-tubule/SR junction. Abnormal Ca release channel in SR. have catastrophic rise in body temp when given volatile anesthetics.
Dantrolene to treat. Dantrolene blocks muscle contraction by blocking Ca release from the SR.
Anesthetic allows Ca to be released w/o depending on conformational change in DHPR… get steady Ca leak from SR. Ca ATPase pumps Ca back into SR, futile heat releasing cycle.
Muscular dysgenesis
Mice are normal when born but can’t breathe and die.
They lack DHP receptor in skeletal m So E-C coupling is interrupted.
Gene therapy works int eh mice.
Cardiac vs. skeletal E-C coupling.
Mouse fine until born and needs skeletal muscles to breathe (muscular dysgenesis). So heart contraction is normal.
Cardiac m also have DHPR and Ca release channels at triad. Why work? Because cardiac DHP is a different gene product, unaffected gene.
Inject mice mutant muscle cells with cardiac gene and they get cardiac E-C coupling (so type of coupling depends on DHP receptor).
How do you terminate muscle response?
Ca ATPase pumps in SR membrane transport Ca back into the SR so intracell Ca conc. falls and you get relaxation.
E-C coupling in cardiac muscle
Cardiac almost identical to skeletal m. in structure and in control of Ca release from the SR.
But Ca entry is required to trigger Ca release by the Ca release channel of the SR (since the cardiac Ca release channel binds ca!!!!…. vs conformational change in DHPR triggering it in skeletal m)
E-C coupling in smooth m.
Does NOT need t-system or SR.
Smooth m. cells are so thin that Ca entering via Ca channels in the surface mem. can easily diffuse to the center of the cell (some smooth m. do have rudimentary SR).
Length-tension
Ca is the major contraction regulation.
Also length is important: if muscle is stretched too much then the actin and myosin do not overlap, no tension generated.
Tension increases linearly as the amount of overlap increases. When actin filaments move into central region of thick filaments, where there are no myosin head groups, tension plateaus.
If shortening causes actin filaments to interdigitate in middle of sarcomere, tension begins to decrease.
Muscle innervation
Each muscle is innervated by a group of motor neurons in the spinal cord. Damage to these motor neurons or to the nerve produces muscle paralysis.
Each motor neuron innervations: one muscle: and in that muscle only a subset of the total muscle fibers.
Motor unit
The muscle fibers innervated by a motor neuron.
Unit because each time motor neuron fires an AP, all the muscle fibers innervated by the neuron contract in unison.
Size of motor units
Varies between and within muscles.
Fine movement muscles have SMALL motor units.
Large muscles have large motor units.
For a single muscle there can be dozens of motor neurons innervating it.
Small motor units are recruited first, progressively larger as contraction increases in strength. This allows fine control of movement.
Cardiac and smooth muscle innervation
They are innervated but can fx. without nervous innervation.
Have innate excitability that is modulated by excitatory and inhibitory innervation.
(in contrast to skeletal muscle that is not electrically coupled, the smooth and cardiac ARE LINKED by gap j’s).
3 classes of skeletal muscle fibers
slow: postural, red colored (high myoglobin)
fast: high glycolytic, rapid activity bursts.
intermediate: fast with glycolytic and oxidative enzymes
They have diff: myosin isoenzymes, diff #’s of mitochondria and oxidative enzymes, diff resistance to fatigue, diff speeds of contraction.
Most muscles are a mix of all 3 types. But EACH MOTOR UNIT is homogeneous.
3 ways to grade skeletal m. tension?
- ) Increase frequency of APs (which increases tension until maximal contraction)
- ) Recruit add’l units until all neurons in use
- ) Change length of the muscle. (not that helpful with skeletal m. because usually operating at optimal length).
Grading tension in smooth/cardiac?
Different, they respond to NT’s and hormones.
Strongly influenced by length of cell (because length is not fixed by bone attachments).
