NROSCI/BIOSCI 1070 MSNBIO 2070 Human Physiology

1. NROSCI/BIOSCI 1070MSNBIO 2070Human Physiology • August 29, 2014 • Muscle 1

2. Sarcolemma = cell membrane Myofibril = basic contractile unit Myofibril comprised of 1500 myosin filaments and 3000 actin filaments Overlap of myosin and actin produces dark A bands Actin alone produces light I band Actin is secured to Z membranes, which pass from myofibril to myofibril (hold everything together) Sarcomere = portion of a myofibril between two Z membranes H zone = band produced when myosin exists without actin (artifact; not in living muscle) Sarcoplasm = muscle cell cytoplasm Sarcoplasmic reticulum = endoplasmic reticulum

3. Define: A band, I band, H zone, Z membrane, sarcomere, mitochondria

4. Mechanism of Muscle Contraction • When muscle contracts, the Z membranes come closer together, and the I zones and sarcomeres decrease in width. No H zone is present. • This is the sliding filament mechanism of muscle contraction.

5. What Causes Muscle Contraction? • Actin appears to be “ratcheted inward” by the actions of the myosin cross bridges • This ratcheting is due to attractive forces between the actin and myosin • The attractive forces are inhibited when muscle is relaxed • The activation of the attractive forces appears to require: Ca++ and ATP

6. Molecular Characteristics of Myosin • Each myosin molecule is composed of 6 polypeptide chains: 2 heavy chains and 4 light chains • The heavy chains form the tail • The light chains in association with the heavy chains form the head • 200 or more myosin molecules form a myosin filament

7. Molecular Characteristics of Myosin • The portion of the myosin tails farthest from the head form the body of the myosin filament • The head and adjacent tail form the cross bridge • The cross bridge is “hinged” at two points: where it emerges from the body and at the junction with the head

8. Molecular Characteristics of Actin • Actin filaments are composed of actin, tropomyo-sin, and troponin • The backbone of the actin filament is comprised of F-actin protein • Along the F-actin helix are active sites where myosin has a high affinity • In the resting state, the tropomyosin strand covers the active sites

9. Molecular Characteristics of Actin • The actin filament also includes troponin, which is comprised of three globular proteins • One of the globular proteins has affinity for actin, another for tropomyosin, and the third for Ca++ • It is believed that when Ca++ binds to troponin, a conformational change occurs, pulling tropomyosin away from the active sites and exposing them. THIS INITIATES MUSCLE CONTRACTION.

10. Interaction of Actin and Myosin to Produce Contraction • As soon as the active sites are uncovered, the heads of the cross bridges immediately attach to the actin molecules at these points. • A configuration change then takes place in the cross bridge, causing the head to tilt while pulling the actin filament along with it. • This tilt of the head of the cross bridge is called the power stroke, and is the major mechanism in muscle contraction. • After the power stroke is completed (and the configuration of the myosin molecule has changed), the myosin is no longer attracted to actin and the two molecules separate.

11. Interaction of Actin and Myosin to Produce Contraction • The myosin then reverts to its original configuration, and its attraction for actin returns. • The myosin head then attaches to the next available active site. • Because many cross bridges are cycling out of phase, when one myosin head detaches the actin does not slip back to its initial position

12. Role of ATP in Muscle Contraction • Most of the muscle contraction proceeds without ATP. The attachment of myosin to actin is not ATP dependent; neither is the resulting change in conformation in the myosin molecule • It is believed that this change in shape of the myosin molecule exposes an ATP binding site. The binding of ATP to this site causes the myosin to be released from the actin. • The ATP molecule then degrades to ADP, and the energy released causes the myosin molecule to return to its original conformation. The myosin is then ready to bind to the next actin binding site.

13. Role of ATP in Muscle Contraction • The rate-limiting step in muscle contraction is breaking of the ATP high energy bond by the enzyme myosin ATPase in the myosin head. The faster that myosin ATPase works to break the high-energy bond, the faster the cross bridges ratchet the actin inwards. • The factor that typically leads to a failure in muscle contraction (muscle ‘fatigue’) is depletion of ATP.

14. Role of ATP in Muscle Contraction • If ATP were to be depleted, as occurs following death, then the actin and myosin molecules would not separate, and would be permanently fixed together. This would cause the muscle length to become fixed, and the muscle would appear to be very stiff. In fact, this phenomenon explains “rigor mortis”. • Like most cells, muscle generates ATP from both glycolysis and oxidative phosphorylation.

15. Creatine Phosphate • Muscle cells often require more ATP than can be produced through typical mechanisms. • Thus, muscle cells have a special immediate precursor for the generation of ATP: creatine phosphate. Creatine phosphate is a high-energy molecule that can re-phosphorylate ADP to ATP. • Creatine phosphate levels drop during muscle contraction; some athletes consume this chemical as a “performance enhancer”.

16. Creatine Phosphate • Creatine can be found in many forms. Muscle contains approximately 0.5% creatine by weight, although some of this will be degraded by cooking. Commercial supplements are also available. It has been suggested that human muscle has a maximum capacity of roughly 150 mmol creatine/kg muscle, making supplementation in excess of 20g/day pointless. • A number of studies have examined the effect of creatine supplementation on performance. The consensus appears to be that, while not increasing peak force production, creatine can increase the amount of work done (8%) in the first few short duration, maximal effort trials. The mechanism of this enhancement is not yet clearly documented, but is most likely by increasing the available pool.

17. Initiation of Muscle Contraction • An action potential that propagates along the sarcolemma induces muscle contraction • The muscle action potential is triggered by the release of acetylcholine from a moto-neuron terminal, at the neuromuscular junction • The activity of the central nervous system tightly controls the initiation of muscle action potentials, and thus muscle contraction

18. Initiation of Muscle Contraction • The muscle action potential quickly propagates deep into a muscle via transverse tubules (T-tubules) • The terminal cisternae of the sarcoplasmic reticulum abut the T -tubules, and become depolarized when an action potential invades.

19. Initiation of Muscle Contraction • The depolarization of the sarcoplasmic reticulum opens voltage-gated Ca++ channels. • Ca++ flows down its concentration gradient into the sarcoplasm, binds to the C (calcium)-troponin subunit, and initiates muscle contraction  After 300 msec, an ATP-dependent pump returns the Ca++ to the sarcoplasmic reticulum, and contraction stops unless another action potential courses along the muscle membrane.

20. Length-Tension Relationship in Muscle • Muscle contracts best when a maximal number of myosin heads can bind to actin. • If the resting length of muscle is too great or too small, the actin-myosin relationships are not optimal and contraction strength diminishes.

21. Length-Tension Relationship in Muscle • This concept can also be applied to a whole muscle. • If the muscle is stretched,tension develops due to elastic com-ponents in the muscle. However, if contraction is induced in a stretched muscle, the tension produced by the contraction will be small due to minimal overlap between actin and myosin at the onset of contraction. • Similarly, if a muscle is com-pressed, very little tension will be produced during contraction because of the altered relation-ship between actin and myosin.

22. Motor Units Motor Unit = Motoneuron + Muscle Fibers it Innervates Muscle Unit=Muscle Fibers Innervated by a Particular Motoneuron How many muscle fibers are innervated by a motoneuron?

24. Synaptic Security at the Neuromuscular Junction is Very High, So Muscle Always Contracts when a Motoneuron Fires Unless Something Goes Wrong:

25. Question for Discussion What is the best treatment for a patient with Myasthenia gravis ?

26. Receptor Subtypes • Binding of a neurotransmitter at one site can have vastly different effects than at another. • Typically, receptors with differing responses to the binding of a particular neurotransmitter also have different configurations, and affinities for that neurotransmitter. • It thus may be possible for a particular drug to bind to one neurotransmitter receptor “subtype” and not another. This is how neurotransmitter subtypes are differentiated.

27. Muscarinic and Nicotinic Acetylcholine Receptors • The acetylcholine receptor has two major subtypes: nicotinic and muscarinic receptors. • The nicotinic receptors bind the plant alkaloid “nicotine,” whereas the muscarinic receptors bind the toadstool toxin muscarine. • The agonist for both receptors in the body is the same (acetylcholine), but the selective affinity of the subtypes for one drug can be exploited by pharmacologists.

28. Nicotinic Receptors • Are composed of 5 protein building blocks. • All the building blocks have a similar chemical structure, but there are some differences. • 12 different building blocks and 17 different types of nicotinic receptors have been discovered. • Depending on the exact combination of building blocks, the affinity of a nicotinic receptor for a particular drug can differ.

29. Affinity of Different Subtypes of Nicotinic Receptors for Drugs

30. Increases in Muscle Force • Muscle force can be increased by two mechanisms: frequency modulation (increasing the discharge rate of the motor unit) or recruitment (activation of inactive motor units). • If a motoneuron fires before the tension produced by the previous contraction has dissipated, then the force of the second contraction will add to the first. • The faster the firing rate of the moto-neuron, the more cumulative force will be produced until the maximal contractile ability of the muscle is reached.

31. Increases in Muscle Force  If a motoneuron fires rapidly enough, a “plateau” of muscle tension will occur. This plateau is referred to as a tetanus.  However, recruitment of new motor units is required for a muscle to develop a reasonable amount of force; there is a limit as to how much force a single motor unit can produce.

32. Distribution of Muscle Fibers Innervated by a Single Motoneuron:

33. Motor Unit Types Initial Differentiation: Red vs. White Muscle (Ranvier)

34. Motor Unit Types

35. Motor Unit Types (Burke): • Slow vs. Fast (S or F designation) • Fast contracting < 55 ms • Slow Contracting > 55 ms • Fatigue Index = % Muscle Tension Retained When Stimulating Continuously for 120 sec • (R {resistant to fatigue} and F {fatigable} designation)

36. Motor Unit Properties

37. Question for Discussion • Would it be possible for FF motor fibers to perform their “job” if they relied on aerobic metabolism? • Why or why not?

38. Relaxation of Muscle • By definition, relaxation occurs when there is no contraction, and the muscle returns to its normal resting length. • This must be done smoothly, but requires no active expenditure of energy. • When the myosin heads disengage from actin, relaxation occurs. This process is “smoothed” by the elastic elements in the body, both in the muscle itself and structures to which it is attached.

39. Clinical note: muscular dystophy