DOWNLOAD PDF STRUCTURE AND REGULATION OF CARDIAC AND SKELETAL MUSCLE THIN FILAMENTS

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1 Chapter 1 : ACTC1 - Wikipedia LARRY S. TOBACMAN STRUCTURE AND REGULATION OF CARDIAC AND The biological production of force and movement can be understood only when it is. Structure[ edit ] There are three different types of myofilaments: Thick filaments consist primarily of the protein myosin. A myosin molecule is shaped like a golf club, with a tail formed of two intertwined chains and a double globular head projecting from it at an angle. Half of the myosin heads angle to the left and half of them angle to the right, creating an area in the middle of the filament known as the bare zone. Each F actin strand is composed of a string of subunits called globular G actin. Each G actin has an active site that can bind to the head of a myosin molecule. Each thin filament also has approximately 40 to 60 molecules of tropomyosin, the protein that blocks the active sites of the thin filaments when the muscle is relaxed. Each tropomyosin molecule has a smaller calcium-binding protein called troponin bound to it. All thin filaments are attached to the Z-line. They run through the core of each thick filament and anchor it to the Z-line, the end point of a sarcomere. Titin also stabilizes the thick filament, while centering it between the thin filaments. It also aids in preventing overstretching of the thick filament, recoiling like a spring whenever a muscle is stretched. In striated muscle, such as skeletal and cardiac muscle, the actin and myosin filaments each have a specific and constant length in the order of a few micrometers, far less than the length of the elongated muscle cell a few millimeters in the case of human skeletal muscle cells. The filaments are organized into repeated subunits along the length of the myofibril. These subunits are called sarcomeres. The contractile nature of this protein complex is based on the structure of the thick and thin filaments. The thick filament, myosin, has a double-headed structure, with the heads positioned at opposite ends of the molecule. During muscle contraction, the heads of the myosin filaments attach to oppositely oriented thin filaments, actin, and pull them past one another. The action of myosin attachment and actin movement results in sarcomere shortening. Muscle contraction consists of the simultaneous shortening of multiple sarcomeres. Acetylcholine diffuses across the synaptic cleft and binds to the muscle fiber membrane. Calcium ions are then released from the sarcoplasmic reticulum into the sarcoplasm and subsequently bind to troponin. Troponin and the associated tropomyosin undergo a conformational change after calcium binding and expose the myosin binding sites on actin, the thin filament. The filaments of actin and myosin then form linkages. After binding, myosin pulls actin filaments toward each other, or inward. Thus muscle contraction occurs, and the sarcomere shortens as this process takes place. Muscle fiber relaxation[ edit ] The enzyme acetylcholinesterase breaks down acetylcholine and this ceases muscle fiber stimulation. Active transport moves calcium ions back into the sarcoplasmic reticulum of the muscle fiber. ATP causes the binding between actin and myosin filaments to break. Troponin and tropomyosin revert to their original conformation and thereby block binding sites on the actin filament. The muscle fiber relaxes and the entire sarcomere lengthens. The muscle fiber is now prepared for the next contraction. Response to exercise[ edit ] The changes that occur to the myofilament in response to exercise have long been a subject of interest to exercise physiologists and the athletes who depend on their research for the most advanced training techniques. Athletes across a spectrum of sporting events are particularly interested to know what type of training protocol will result in maximal force generation from a muscle or set of muscles, so much attention has been given to changes in the myofilament under bouts of chronic and acute forms of exercise. While the exact mechanism of myofilament alteration in response to exercise is still being studied in mammals, some interesting clues have been revealed in Thoroughbred race horses. Researchers studied the presence of mrna in skeletal muscle of horses at three distinct times; immediately before training, immediately after training, and four hours after training. They reported statistically significant differences in mrna for genes specific to production of actin. This study provides evidence of the mechanisms for both immediate and delayed myofilament response to exercise at the molecular level. Again, researchers are not completely clear about the molecular mechanisms of change, and Page 1

2 an alteration of fiber-type composition in the myofilament may not be the answer many athletes have long assumed. This study concludes that there is no clear relationship between fiber-type composition and in vivo muscle tension, nor was there evidence of myofilament packing in the trained muscles. Research[ edit ] Other promising areas of research that may illumine the exact molecular nature of exercise-induced protein remodeling in muscle may be the study of related proteins involved with cell architecture, such as desmin and dystrophin. These proteins are thought to provide the cellular scaffolding necessary for the actin-myosin complex to undergo contraction. Research on desmin revealed that its presence increased greatly in a test group exposed to resistance training, while there was no evidence of desmin increase with endurance training. According to this study, there was no detectable increase in dystrophin in resistance or endurance training. While the research on muscle fiber remodeling is on-going, there are generally accepted facts about the myofilament from the American College of Sports Medicine. However, there is some evidence of animal satellite cells differentiating into new muscle fibers and not merely providing a support function to muscle cells. The weakened contractile function of skeletal muscle is also linked to the state of the myofibrils. Furthermore, cellular and myofilament-level adaptations are related to diminished whole muscle and whole body performance. Page 2

3 Chapter 2 : Cardiac thin filament regulation In general, skeletal muscle contractile proteins lack the functional phosphorylation targets found in the cardiac contractile protein isoform counterparts, a finding that is consistent with the fundamentally different cellular mechanisms underlying regulation of contractile force between cardiac and skeletal muscle. The neuromuscular junction will also be discussed. Skeletal Muscle It is composed of an orderly arrangement of connective tissue and contractile cells. The epimysium is the external connective tissue wrapping around the entire muscle. The skeletal muscle is made up of fascicles. Fascicle Fascicles are bundles of individual muscle cells which make up a skeletal muscle as shown in Figure 1. These fascicles are surrounded by a connective tissue layer called the perimysium. There is a third connective tissue called the endomysium which separates and electrically insulates muscle cells from each other. A skeletal muscle with associated connective tissues, showing structures all the way down to myofilaments. Muscle Cell Fibre Muscle cell fibres are so called because they are elongated. Its cell membrane is called the sarcolemma and the fibres have sarcoplasmic reticulum, which is its endoplasmic reticulum. T-tubules are the invagination of sarcolemma projecting deep down into the muscle cells. Structure of a skeletal muscle fibre containing myofibrils. Myofibril Myofibrils are the cylindrical bundles of contractile filaments. These individual contractile proteins are called myofilaments which are composed of thick and thin filaments. They form repeating units along the myofibril which are termed sarcomeres. Sarcomere The sarcomere is a functional contractile unit of a myofibril. Actin filaments - The thin filaments that consist of two intertwined chains of G actin molecules called troponin and tropomyosin. Tropomyosin is filamentous in structure and it coils around this actin filament. Troponin is a three part protein attached to the tropomyosin filaments. This is illustrated in Figure 4 to the right. Myosin filaments - The thick filaments that consist of to myosin molecules bundled together with the heads projecting outward in a spiral array. A single myosin molecule is composed of two intertwined polypeptides forming a filamentous tail and a double globular head, as shown in Figure 4. Molecular structure of thick and thin filaments. Actin and myosin filaments are abundant in skeletal and cardiac muscles which account for their striations. These striated muscles have dark A bands and lighter I bands as shown in Figure 5. The dark A-band has two parts. The darker area is where myosin filaments overlap actin filaments. H band is the lighter region in the middle of A band where the actin filaments do not reach. The I band consists of thin actin filaments anchored to Z-discs composed of connectin proteins bisecting through this I band. Sarcomere is the segment of myofibril from one Z-disc to the next one as shown in Figure 3. Z-discs are connected to the sarcolemma muscle cell plasma membrane by cytoskeleton. Individual sarcomeres shorten, bringing Z-discs closer to each other. The pulling of the sarcolemma achieves an overall shortening of a cell. Five myofibrils of a single muscle fibre, showing the structure of sarcomeres and striation in relaxed state. Neuromuscular junction The neuromuscular junction is a synapse between a nerve fibre and a muscle fibre. Two neuronal cells are separated by a tiny gap called the synaptic cleft about nm wide. A Schwann cell envelopes the entire neuromuscular junction, isolating it from surrounding tissue fluids. It prevents an electrical signal travelling down the nerve fibre from crossing the synaptic cleft; rather, it causes the nerve fibre to secrete a synaptic vesicle containing a neurotransmitter that stimulates the next cell. Acetylcholine is the only transmitter released at neuromuscular junction. After a brief time, the acetylcholine diffuses away from their receptor sites causing ion channels to close. Page 3

4 Chapter 3 : Ultrastructure of Muscle - Skeletal - Sliding Filament - TeachMeAnatomy Due to its irregular arrangement of actin and myosin filaments, smooth muscle does not have the striated appearance of skeletal muscle. In addition, the sarcolemma does not form a system of transverse tubules. General News Scientists from Italy and the United Kingdom, in collaboration with the ESRF, have demonstrated a new regulation mechanism which provides a novel explanation for the dynamic and energetic properties of skeletal muscle. These findings offer a promising approach for new investigations on the regulation of cardiac muscle and new therapeutic opportunities. Contraction of striated muscles skeletal and cardiac muscles was thought to be controlled by a calcium-dependent structural change in the actin-containing thin filaments that permits the binding of myosin motors from the neighbouring thick filaments to drive filament sliding. By synchrotron X-ray diffraction from single skeletal muscle cells, the scientists have shown that muscle contraction is actually controlled by two switches. They demonstrated that, although the well-known thin-filament mechanism is sufficient for regulation of muscle shortening against low load, force generation against high load requires a second permissive step linked to a change in the structure of the thick filament. This concept of the thick filament as a regulatory mechano-sensor provides a novel explanation for the dynamic and energetic properties of skeletal muscle. A similar mechanism is likely to operate in the heart, another striated muscle. This fundamental result, published in Nature, therefore offers a promising approach for new investigations on the regulation of the cardiac muscle and new therapeutic opportunities. Picture and schema of the experimental set-up with the muscle cell mounted vertically in a trough between the loudspeaker motor bottom and the force transducer top. Striated muscles skeletal and cardiac muscles contract by the relative sliding motion of two sets of overlapping filaments containing the proteins actin and myosin. According to the textbook view, contraction is triggered by the rise of the concentration of calcium ions that follows excitation of the muscle cell by a motor nerve. Binding of calcium ions to regulatory proteins in the thin actin filament releases them from their inhibitory action, allowing myosin motors from the thick myosin filament to attach and pull the actin filament in the shortening direction. An international team of scientists from Italy, the UK and France has now demonstrated a new regulatory mechanism. For this discovery, they used small-angle X-ray diffraction from the intense light source of the ESRF to observe at the molecular scale how muscle proteins change structure inside a contracting skeletal muscle cell. This new regulatory mechanism allows the number of myosin motors to be adapted to the force developed by the contraction. When the load is low, the action of a small fraction of the motors drives muscle shortening at high velocity within a few milliseconds of the excitation, when calcium ions have activated the actin filament. When the load is high, the mechano-sensing property of the myosin filament is responsible for recruitment of the much larger fraction of motors required to generate a high force. From left to right: Reconditi University of Florence, and G. Steinen University of Amsterdam, not involved in this research project. Argoud What is the significance of this new mechanism of regulation? However that view became increasingly difficult to reconcile with emerging evidence that the myosin motors in resting muscle are immobilised or switched OFF and cannot interact with actin. How could such a switched OFF myosin motor sense the state of the actin filament at a distance? The new results provide an answer: Not only can this small fraction of motors drive unloaded shortening with high metabolic efficiency, but they also have a signalling function: This discovery opens the possibility of new approaches for therapeutic control of cardiac output. Vincenzo Lombardi, from University of Florence and co-author, says: However, this is not the only way the myosin motor regulates its activity. Other contractile systems, like smooth muscle, which do not require a fast response, use an intra-molecular mechanism of regulation that consists of an increase in the level of phosphorylation of the regulatory portion of the motor itself. Presently we are striving to optimise this technique for cardiac muscle. Wikiversity Journal of Medicine. Page 4

5 Chapter 4 : Change of paradigm for skeletal muscle regulation Structure of cardiac muscle. The fundamental contractile unit in both skeletal and cardiac muscle is the sarcomere ().These units are about 2 μm long and are defined at each end by the Z line which is formed from the protein α-actinin. The entire muscle, as well as the individual cells, are wrapped in collagen. Near the end the collagen merges to form the tendons, which attach the muscle to the bone. It is through this connective tissue that the force generated by the individual cells is transmitted to the bone. A group of muscle cells are bundled together by collagen to form a fascicle. Since muscle cells are elongated and cylindrical, each muscle cell is usually called a muscle fiber. In skeletal muscle, the muscle fibers are very large, multinucleated, and up to several millimeters in length. Looking at one muscle fiber, you will see that almost the entire cross section of the muscle fiber is taken up by long, cylindrical strands of contractile proteins called myofibrils. Typically there are hundreds of these in one cross section of a muscle fiber. Looking at one myofibril, we see that it is divided into segments called sarcomeres. These are the contractile units of a muscle. A dark stripe called a Z disc marks the ends of one sarcomere and the beginning of the next. Sarcomeres are composed of thick filaments and thin filaments. The thin filaments are attached at one end to a Z disc and extend toward the center of the sarcomere. The thick filaments, by contrast, lie at the center of the sarcomere and overlap the thin filaments. Look at the diagram above and realize what happens as a muscle contracts. The thick and thin filaments slide with respect to one another, using ATP as a source of energy. As a result of the sliding, the Z discs are pulled closer together. This is called the sliding filament mechanism. The contraction of a whole muscle fiber results from the simultaneous contraction of all of its sarcomeres. The contraction of a muscle fiber is triggered by an action potential conducting over plasma membrane of the muscle fiber. The action potential conducts from the surface of the muscle fiber into the interior via transverse tubules T tubules. These long tubes are continuous with the plasma membrane. As a T tubules passes each myofibril, it touches, but is separate from, membranous bags called the sarcoplasmic reticulum. This causes the filaments to start sliding and thus the sarcomere to shorten. The thick filaments are comprised of an elongated protein called myosin. Each myosin molecule is shaped like a golf club, with the head of the golf club pointed out from the surface of the thick filament. This structure will form the cross bridge that binds to the thin filament. Actin is the main protein of the thin filament. A second protein, called troponin, is found at intervals. The cross bridges then pull on the thin filaments, causing the sarcomere to shorten. The cross bridges then release the actin, with one molecule of ATP used by each cross bridge in each cycle. Next to each muscle fiber are a few small satellite cells, which retain some of the embryonic characteristics. Notably, they can fuse with damaged muscle fibers and help repair the damage. Chapter 5 : Thin Filament : Muscle Components & Associated Structures : IvyRose Holistic A rapid mechanism for contraction, as required in cardiac muscle, is not important for smooth muscle true The large number of steps involved in regulating vascular smooth muscle contraction allows for many possible sites for regulation including. Chapter 6 : Structure of Cardiac and Smooth Muscle Each muscle cell (also known as a ' muscle fibre ') contains many specialised components described on the page about the structure of a muscle cell. Key functional components within muscle cells include myofibrils, which consist of two types of protein filaments called ' thick filaments ', and ' thin filaments '. Page 5

6 Chapter 7 : Skeletal Muscle :: Sliding filament theory Thin (actin) filament accessory proteins are thought to be the regulatory force for muscle contraction in cardiac muscle; however, compelling new evidence suggests that thick (myosin) filament regulatory proteins are emerging as having independent and important roles in regulating cardiac muscle contraction. Chapter 8 : CARDIAC MUSCLE STRUCTURE AND FUNCTION Clinical Gate A thin filament is one of the two types of protein filaments that, together form cylindrical structures call myofibrils and which extend along the length of muscle fibres. Thin filaments are formed from the three proteins actin, troponin and tropomyosin. Chapter 9 : Myofilament - Wikipedia New perspectives for the regulation of cardiac muscle. As thick filament structure and protein composition are essentially the same in heart and skeletal muscle, thick filament mechano-sensing may. Page 6