True or false: Muscle cells convert chemical energy in the form of ATP into mechanical energy-contraction and heat.
The globular heads of the myosin molecules (with ATP and actin binding sites) are called ___ ___.
Describe what occurs during skeletal muscle contraction.
1. When myosin is in a relaxed state (cocked), it is energized with a bound ADP and Pi. The myosin cross bridges are engergized and ready to bind to actin. When Ca2+ released from the sarcoplasmic reticulum binds to TnC, tropomyosin flexes off of actin exposing the myosin binding sites.
2. Myosin binds to actin (cross bridge state), releases Pi, and the powerstroke occurs, bringing actin filament inward. ADP is released after the powerstroke.
3. ATP (with Mg2+) comes in and binds to the myosin head and myosin is released from actin. Myosin is again in the cocked state.
Each time contraction occurs, myosin heads bind to an even more distal actin molecule, causing muscle shortening (H and I bands shorten therefore shortening the whole sarcomere, Z lines come closer together). Note that if there is no ATP available to bind to the myosin cross bridges, they remain bound to actin, referred to as a rigor complex.
please see slide 8 of notes
Describe what is involved in muscle relaxation as it pertains to Ca2+.
After an AP causes Ca2+ release channels in the SR to open, they will (provided a second AP does not arrive) close within ~10 ms. The SR membrane contains a high density of Ca2+ ATPase pumps that use ATP to pump Ca2+ from the cytosol back into the SR. The pump is stimulated by the increased cytosolic [Ca2+]. Once the SR Ca2+ release channel is closed, cytoplasmic Ca2+ concentration falls to its low resting value within 50-100 ms. Additionally, parvalbumin is involved in muscle relaxation through its ability to rapidly bind Ca2+ which is shortly returned to the SR. Parvalbumin is considerably more abundant in fast (white) fibers and contributes to their more rapid relaxation. In total, the duration of tension in skeletal muscle resulting from a single AP is typically about 50-100 ms. The duration depends on the the type of muscle fiber. Note that this is much longer than the 1-2 ms duration of the AP that stimulated contraction in the first place.
What is malignant hyperthermia (anesthetic hyperthermia)?
the SR Ca2+ release channel in skeletal muscle becomes stuck open after an AP
Where do the products of acetylcholinesterase go after its action?
Into the presynaptic neuron for synthesis of more ACh
Discuss the effects of black widow spider venom on the NMJ.
causes explosive release of ACh
Discuss the effects of Clostridium botulinum toxin
on the NMJ. What is this used for clinically?
blocks ACh release. Used in Botox
Discuss the effects of Lambert-Eaton myasthenic syndrome on the NMJ. What is one of the sx?
Auto-immune disease where antibodies against pre-synaptic Ca2+ channels are produced, resulting in diminshedCa2+ influx into the pre-synaptic terminal. This results in reduced ACh release. sx include muscle weakness.
Discuss the effects of curare on the NMJ.
curare competively (reversibly) binds ACh receptors
Discuss the effects of Myasthenia gravis on the NMJ. What is one of the sx?
Auto-immune disease where antibodies are produced against ACh receptors causing their endocytosis and destruction. Results in varying degrees of muscle weakness
Discuss the effects of organophosphates (certain pesticides, military nerve gases) on the NMJ.
irreversibly inhibit acetylcholinesterase
Discuss the effects of neostigmine on the NMJ.
temporarily inhibits acetylcholinesterase
True or false: At the junction btwn the A and I band (twice for each sarcomere) the sarcolemma invaginates ino the cell fto form a mesh of tubules that run perpendicular to the long axis of the fiber called T-tubules. These planar meshes of tubules run twn myofibrils and penetrate to the center of the muscle fiber. Because T-tubules are continuous with the surface membrane, an AP propagating along the surface of the fiber will also propagate into the T-tubule and thus to the center of the fiber.
The process by which electrical excitation of the muscle fiber leads to contraction of the muscle fiber is known as what?
excitation-contraction coupling (EC) coupling
The SR forms an interconnected network of tubules that surround all of the myofibrils. Near the plane of each network of T-tubules, the
SR enlarges into structures called what? (hint: there are 2 names for them)
terminal cisternae or lateral sacs
Discuss the mechanism of Ca2+ release from the SR.
When an AP occurs in the T-tubule membrane, it triggers Ca2+ release from the SR (remember in skeletal muscle, T-tubules are closely associated with 2 terminal cisternae/lateral sacs of the SR forming triads). The region in which the T-tubule membrane comes into close proximity with the lateral sacs of the SR is called the T-SR junction. In this region, the T-tubule membrane contains a high density of dihydropyridine (DHP) receptors. DHP receptors are related to VG Ca2+ channels and although they do allow for a small amount of Ca2+ current, their main role is in voltage sensing. They constitute the voltage sensors of EC coupling. The membrane of the lateral sacs of the SR contains ryanodine receptors (RyR) that align with the DHP receptors of the adjacent T-tubule membrane. RyR are the Ca2+ releasing channels of the SR. Exactly how the DHP receptors cause Ca2+ release from RyR receptors is not entirely understood but there is evidence that this is done through mechanical coupling. Depolarization of the T-tubule membrane by an AP causes a conformational change in the DHP receptor (voltage sensor) which in turn causes the openig or RyR allowing for Ca2+ to be released into the cytosol from the SR. Note that the strucutral arrangement of the T-tubules, SR, and myofibrils assures that Ca2+ does not have to diffuse more than about 1 micron to reach any point in the contractile machinery of the muscle fiber. pg 38 of notes puts everything together from AP to cross-bridge cycling and contraction
Skeletal muscle weakness is an important feature in numerous pathological conditions that are most of the time, associated with pai. Despite the differenty types of molecular triggers and signaling pathways involed, there will be consistent morphological and physiological changes. What are those changes?
decreased protein content
decreased fiber diameter
decreased force production
decreased fatigue resistance
decreased muscle mass (musle atrophy)
What processes are associated with skeletal muscle weakness?
normal aging process: conseqeunce of lifestyle with too little phyiscal activity, among other things related to aging
genralized disorders: general inflammatory diseases, cancer, in association wit intensive care tx (immobilization, muscle unloading, denervation)
primary muscle diseases: inherited myopathhies, muscular dystrophies
Discuss the role of the dystrophin-glycoprotein (DCG) complex in skeletal muscle and what diseases alterations in this complex may lead to.
Dystrophin binds to non-sarcomeric actin in the cytoskeleton of muscle at one end and to elebments of te dystrophin-glycoprotein complex embedded in the surface membrane of the muscle cell at the other end. Dystrophin and DCG from an important lingkage btwn the actin membrane cytoskeleton, the membrane itself, and the ECM. A vital fxn of dystrophin and the DCG appears to be the stabilization of the periphery of the muscle cell during contraction. Disruptions of the DCG render muscle fibers more susceptible to necrosis and thus lead to muscle wasting. Primary defects in dystrophin and the DCG are responsible for several forms of muscular dystrophy and cardiomyopathy.
The force exerted on an object by a contracting muscle is known as muscle ___ while the force on the muscle exerted by the weight of an object is the ___. Whether or not force generation leads to fiber shortening (concentric contraction) or lengthening (eccentric contraction) depends upon the relative magnitudes of these 2 properties.
Define the 3 types of skeletal muscle contraction.
isotonic: muscle tension stays the same while length of muscle shortens. The tension outweighs the load and shortening of the muscle allows for the load to be moved. This is a concentric contraction.
isometric: muscle length stays the same while muscle tension increases. Muscle is prevented from shortening and tension is developed with muscle at a constant lenght. Muscle tension equals the opposing load.
eccentric: the load outweighs tension and causes muscle length to increase in spite of opposing force being produced by cross bridges. Muscle tension is less than the opposing load. When extensor muscles in thighs are used to lower you to a seat from a standing position, these muscles lengthen
True or false: The muscle tension is proportional to the number of active cross-bridges that can interact with the thin filament in each half sarcomere.
Discuss the length tension relationship in skeletal muscles.
The resting length of a skeletal muscle fiber in the body is normally near is optimal length, or the length at which maximum tension is developed. The length at which max tension is developed corresponds to the situation in which the overlap of thick and thin filaments is optimal.The amount of tension that can be developed is decreased as the muscle fiber's length is increased or decreased from its optimal length. Skeletal muscle fibers normally only operate in a range from about 70-130% of their resting length.
As fiber legnth increases beyond optimum, developed tension falls essentially linearly bc as fiber is stretched, thin filaments are pulled out from thick filaments and th region of overlap decreases. Less actin is available to bind to cross-bridges of thick filaments. If the msucle is stretched enough, there is no longer any overlap of thick and thin filaments and no active tension can be produced.
As fiber length is decreased below optimal length, tension is also reduced for several reasons. One, as lenght decreases, thin filaments from opposite sides of the sarcomere begin to overlap and this reduces the number of actin binding sites available for cross-bridge binding. If a cross-bridge from one side of the sarcomere binds to acting from the opposite side no tension is produced. Also, with further shortening, ends of thick filaments bump into Z-lines. Finally, its also believed that when muscle shortens to less than about 80% of its optimal length, Ca2+ release from the SR is reduced.
Describe the force-velocity/load-velocity relationship.
The smaller the load, the larger the shortening and the faster the velocity of contraction. At zero load, maximal cycling rate of the cross-bridges is acheived. AT lower loads, the muscle tension generates isotonic shortenings but when load exceeds tension, eccentric contraction occurs.
What mechanisms determine the amount of tension in single skeletal muscle fibers?
1. The length at the onset of contraction
2. The frequency of stimulation
3. fiber diameter (larger fibers can produce more force than smaller fibers)
4. fiber type
5. extent of fatigue
What 2 things determine the strength of contraction of a whole skeletal muscle?
1. changing the tension developed by individual fibers within the muscle
2. changing the number of fibers contracting. this depends on innervation of the muscle (motor unit recruitment)
Discuss changing muscle tension by chaning frequency of stimulation.
Recall that the muscle AP lasts 1-2 ms while the duration of the twitch is btwn 50 and 100 ms. The term twitch refers to the contraction of a muscle fiber resulting from a single AP. A brief refractory period occurs after the end of an AP but a second AP can occur long before the end of the period of force development that results from the first AP. If a second AP ocurrs before the muscle fiber has completely relaxed, there is a summation of twitches. When the muscle muscle fiber is timulated so rapidly that it does not have a chance to relax btwn APs a maximal sustaind contraction results called tetanus
Discuss motor units as it relates to whole muscle tension. Be sure to discuss the size principle and asynchronous recruitment of motor units. Also discuss what kinds of motor units are recruited first as it pertains to fiber types.
An AP in a given motor neuron will normally cause all of the muscle fibers in its motor unit to contract simultaneously. The number of fibers per motor unit and the number of motor units recruited influences the strength of whole muscle contraction. When the CNS recruits motor units for an activity it beings with more easily excited, least powerful small motor units and progresses to more difficult to excite, most powerful large motor units. This is called the size principle. During a sustained contraction when only a portion of motor units are needed for a sub-maximal whole muscle contraction, the body uses a scheme called asynchronous recruitment of motor units. Motor unit activity is alternated, giving some motor units a chance to rest while some other motor units take over. Must be finely coordinated so sustained contraction remains smooth. Is very common in postural muscles but also used in other skeletal muscles. During light to moderate activities, the fatigue-resistant motor units are recruited frist. If activity is very prolonged and/or very intense, the last motor units to be recruited are the fatigue-prone (fast-glycolytic) fiber types.
How is creatine phosphate used for energy generation?
The most readily available pool of energy is the high-energy bond of creatine phosphate. The enzyme creatine phosphotransferase transfers the high engery phosphate of phosphocreatine to ADP, thus reforming ATP.
What processes do muscles need to use ATP for?
1. cross-bridge cycling during contraction (1 ATP/bridge cycle)
2. SR Ca2+ ATPase (1 ATP/Ca2+ pumped)
3. Na+/K+ pump to maintain Na+/K+ ion gradients
What is oxygen debt?
At the end of muscle activity, creatine phosphate and glycogen stores will have decreased and will need to be replenished. These processes require enrgy and a muscle continues to consume oxygen at an increased rate (oxygen debt) for some time after its activy has stopped.
What is muscle fatigue? What is it determined by?
When a skeletal muscle is repeatedly stimulated, the maximal tension that the muscle can produce will eventually decrease. This decline in tension is called muscle fatigue. When muscles are fatigued, decreased shortening velocity and a slower rate of relaxation are also observed. The rate and onset of fatigue depends on skeletal muscle fiber type and intensity and duration of the stimulation.
How may different fiber types be characterized?
basis of maximal velocities of shortening (fast or slow), major biochemical pathway used to form ATP (oxidative phosphorylation or glycolysis) or specific myosin profiles, esp myosin heavy chain isoform complement-muscle fibers that either contain a single myosin heavy chain isoform (pure fiber types) or two or more myosin heavy chain isoforms (hybrid fiber types)
What are the 3 fiber types and what are their characteristics? Where in the body are they found/what types of jobs do they typically do?
Type I (slow-oxidative fibers): found in muscles specialized for maintaining low-intensity contractins for long periods of time without fatigue such as muscles of the back and legs tha support body against gravity. Have high oxidative capacity due to numerous mitochondria and high capillary density and consequently have low fatigability. Also contain myoglobin-red in color
Type IIa (fast oxidative-glycolytic fibers): share characteristics with other 2 fiber types. contract more rapidly thantn slow oxidative fibers and can maintain contraction for a longer period of time than fast-glycolytic fibers. have medium oxidative capacity with moderate fatigability
Type IIb (fast glycolytic fibers): found in msucles adapted for performing high intensity contraction for short periods of time such as arm muscles sued to lift heavy objects. Have little myoglobin (and are sometimes called white fibers). Have low oxidative capacity due to haveing few mitochondria and low capillary denisty. Consequently have high fatigability.