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HKMU FOM INTRODUCTION -Current understanding of the molecular events underlying muscle contraction is embodied in the sliding filament model of muscle contraction. The model is applicable to smooth, skeletal, cardiac, and other contractile activity, including mechanochemical events such as single cell locomotion and receptor endocytosis The biochemical characteristics and biochemical basis of some common pathophysiological states of muscle, includE fatigue and rigor mortis Skeletal muscles comprise about 40% of the mass of the average human body and are formed of long multinucleate, cylindrical cells called muscle fibers actin thin filaments and myosin thick filaments are arranged to form the myofilaments of a sarcomere, continuing with the formation of myofibrils from many myofilaments The plasma membrane of muscle fibers is known as the sarcolemma. Each muscle is made up of bundles of these fibers, or cells, embedded in a matrix of connective tissue known as the endomysium. The bundle of fibers with its endomysium is surrounded by a more fibrous connective tissue sheath known as the perimysium. The composite of the perimysium and its contents is known as a fasciculus. A complete muscle consists of numerous fasciculi surrounded by a thick outer layer of connective tissue known as the perimysial septa The translation of contractile activity of individual muscle fibers to anatomical motion take place through this continuous system of connective tissues and sheaths. Within the sarcolemma is the sarcoplasm, containing all the usual subcellular elements plus long prominent myofibrils. Each myofibril is composed of bundles of filamentous contractile proteins, some extending from end to end in the cell. Myofibrils are the most conspicuous elements in skeletal myofibers making up about 60% of myofiber protein. A single myofibril is composed of many short structural units, known as sarcomeres, which are arranged end to end The proteins at the junctions between sarcomeres form the Z line, and thus a sarcomere extends along a myofibril from one Z line to the next Z line ( Dermacation). Sarcomeres are composed mostly of actin thin filaments and myosin thick filaments. Sarcomeres represent the minimal contractile unit of a muscle It is the coordinated contraction and elongation of millions of sarcomeres in a muscle that gives rise to mechanical skeletal activity. Organization of Contractile Proteins in Muscle THICK FILAMENT: Composed of hundreds of long, contractile myosin molecules arranged in a staggered side by side complex. THIN FILAMENT: Composed of a linear array of hundreds of globular, actin monomers in a double helical arrangement. SARCOMERE The unit of contractile activity composed mainly of actin and myosin and extending from Z line to Z line in a myofibril. Myofibril End to end arrays of identical sarcomeres. Myofiber A single multinucleate muscle cell containing all the usual cell organelles plus many myofibrils. Muscle Organized arrays of muscle fibers. ORGANIZATION OF THE SARCOMERE The organization of individual contractile proteins making up a sarcomere is a key feature of the sliding filament model. Each sarcomere is composed of hundreds of filamentous protein aggregates, each known as a myofilament TWO KINDS OF MYOFILAMENTS Are identifiable on the basis of their diameter and protein composition Thick myofilaments are composed of several hundred molecules of a fibrous protein known as myosin Thin myofilaments are composed of two helically interwound, linear polymers of a globular protein known as actin. Proteins of the Z line, including a-actinin, serve as an embedding matrix or anchor for one end of the thin filaments, which extend toward the center of sarcomeres on either side of the Z line The Z line proteins often appear continuous across the width of a muscle fiber and seem to act to keep the myofibrils within a myofiber in register. The distal end of each thin filament is free in the sarcoplasm and is capped with a protein known as b-actinin. The M-line, which is centrally located in sarcomeres. Like Z line protein, the M line protein aggregate acts as an embedding matrix, in this case for the myosin thick filaments. Thick filaments extend from their point of attachment on both sides of the M line toward the two Z lines that define a sarcomere. During contraction and relaxation the distance between the Z lines varies, decreasing with contraction and increasing with relaxation. The M line, with its attached thick filaments, remains centrally located in the sarcomere The thin and thick filaments retain their extended linear structure Changes in sarcomere length are caused by the thin filaments being pulled along the thick filaments in the direction of the M line. PROTEINS OF THE MYOFILAMENTS The biochemical basis of muscle activity is related to the enzymatic and physical properties of actin, myosin, and the accessory proteins that constitute the thin and thick filaments The proteins of the thin and thick filaments can be separated into actin, myosin, and accessory proteins. The accessory proteins include b-actinin, tropomyosin, troponin C and M line protein. Solubilized myosin molecules are long thin (fibrous) proteins with a molecular weight of about 500,000 daltons. Organization of Actin Thin Filaments Thin filaments are composed of many subunits of the globular protein actin (42 kD) and several accessory proteins. In thin filaments, Actin is polymerized into long fibrous arrays known as F-actin A pair of linear F-actin arrays is helically wound to form the backbone structure of 1 complete thin filament. In relaxed muscle, each tropomyosin molecule covers the myosin binding sites of 7 G-actin residues, preventing interaction between actin and myosin and thus maintaining the relaxed state. The onset of contractile activity involves activating troponin, the second accessory protein of thin filaments Troponin is a heterotrimer attached to one end of each tropomyosin molecule and to actin, physically linking tropomyosin to actin. Conformational changes in the bridging molecule, troponin, are responsible for moving tropomyosin on and off myosin binding sites of actin and thus regulating muscle contraction . One of the troponin subunits, troponin-C (Tn-C), is a calmodulin-like calcium-binding protein. When Tn-C binds calcium, the whole troponin molecule undergoes the conformational change that moves the attached tropomyosin away from the myosin binding sites on actin This event permits nearby myosin heads to interact with myosin binding sites, and contractile activity ensues. Events on the thin filament can be summarized as follows: Prior to the appearance of free calcium in the sarcoplasm, tropomyosin covers the myosin binding sites on actin. The appearance of calcium in the sarcoplasm leads to calcium binding on Tn-C. The resulting conformational changes in troponin uncovers the myosin binding sites on G-actin subunits. The exposed sites are then available to interact with myosin headpieces. Removing calcium from the sarcoplasm restores the original conformational states of troponin and tropomyosin, preventing interaction between actin and myosin and leading to the relaxed state Myosin and the Power Stroke of Contraction - In a rested, non-contracting muscle, myosin binding sites on actin are obscured and myosin exists in a high-energy conformational state (M*), poised to carry out a contractile cycle The energy of ATP hydrolysis is used to drive myosin from a low-energy conformational state (M) to the high-energy state, as illustrated in Equation 1. (M-ATP) <-----> (M*-ADP-Pi) Eqn. 1 When cytosolic calcium increases and myosin binding sites on actin become available, an actomyosin complex is formed, followed by the sequential dissociation of Pi and ADP with conversion of myosin to its low-energy conformational state. These events are accompanied by simultaneous translocation of the attached thin filament toward the M line of the sarcomere. The latter events, summarized in Equations 2 and 3 comprise the power stroke of the contractile cycle Note that the energy of the power stroke is derived from ATP, via ATP-driven conversion of a low-energy myosin conformational state to a high-energy conformational state. A useful analogy is that ATP cocks the myosin trigger and the formation of an actomyosin complex pulls the trigger, releasing the energy stored in cocking the trigger. (M*-ADP-Pi) + A <----> (M*-ADP-A) + Pi (M*-ADP-A) <-----> (M-A) + ADP Eqn. 2 Eqn. 3 At the end of the power stroke the actomyosin complex remains intact until ATP becomes available ATP binding to myosin is a very exergonic reaction, with the result that ATP displaces actin from the myosin head as indicated by Equation 4. Thus it is often said that ATP is required for muscle relaxation. It is important to note that in relaxed muscle, myosin is in its high-energy conformational state. Note that in Equation 4 the final product (M-ATP) is also the first reactant shown in Equation 1, completing the reactions of the contractile cycle. (MA) + ATP <------> (M-ATP) + A Eqn. 4 A diagrammatic illustration of the reactions described in equations 1 through 4, as they occur in muscle, is shown below The process of reactions that occur leading to muscle contraction. A contractile cycle begins with myosin in a high energy conformation depicted by A. The power stroke begins with actin binding myosin in the A conformation and ends with formation of a low energy actomyosin complex, depicted in C. The complex is broken by ATP binding (step C to D) and the high energy conformation of myosin regenerated by ATP hydrolysis (D to E). Notice that the conformation of myosin in A and E is identical. PROCESS OF REACTIONS THAT OCCUR LEADING TO MUSCLE CONTRACTION. A contractile cycle begins with myosin in a high energy conformation depicted by A. The power stroke begins with actin binding myosin in the A conformation and ends with formation of a low energy actomyosin complex, depicted in C. The complex is broken by ATP binding (step C to D) and the high energy conformation of myosin regenerated by ATP hydrolysis (D to E). Notice that the conformation of myosin in A and E is identical. Regulation of Sarcoplasmic Calcium Events that stimulate muscle activity by raising sarcoplasmic calcium begin with neural excitation at neural muscular junctions Excitation induces local depolarization of the sarcolemma, which spreads to the interior of the myofiber T tubule depolarization spreads to the sarcoplasmic reticulum (SR), with the effect of opening voltage-gated calcium channels in the SR membranes. This is followed by massive, rapid movement of cisternal calcium into the sarcoplasm close to nearby myofibrils. The appearance of calcium very close to the Tn-C subunit of troponin results in the production of multiple myosin power strokes, as long as the available calcium concentration remains greater than about 1 to 5 micromolar. Muscle Relaxation: Normally, cessation of contractile activity and a state of relaxation follow electrical quiescence at the myoneural junction. Then The sarcoplasmic membrane returns to its resting electrical potential. Subsequently, sarcoplasmic calcium is pumped back into the SR cisternae by an extremely active ATP- driven calcium pump, which comprises one of the main proteins of the SR membrane. The cisternal surface of the SR membrane also contains large quantities of a glycoprotein known as calsequestrin. Calsequestrin avidly binds calcium, decreasing its concentration in the cisternae, and thus favoring calcium accumulation A final repository of sarcoplasmic calcium is the mitochondrial matrix. Mitochondria have a remarkably active calcium pump. Under aerobic conditions this pump uses the energy of electron transport to sequester calcium in the mitochondrial matrix, in preference to the synthesis of ATP SOURCES OF ATP FOR MUSCLE CONTRACTION 1.Glycolysis 2.TCA. 3. ETC 4. creatine phosphate (CP) 5. and ADP. CP + ADP ------> Creatine +ATP creatine kinase ADP + ADP -------> AMP + ATP Adenylate kinase Since tetanic stimulation raises sarcoplasmic calcium and depletes ATP, the end result is a highly contracted muscle with calcium bound to Tn-C and no ATP available to resequester calcium into the cisternae of the SR, nor to break actomyosin cross-bridges The absence of ATP results in myosin remaining in its low-energy conformational state, with the result that new cycles of muscle stimulation will result in only limited ability of the muscle to generate contractile activity. Muscles in this physiological state are said to be fatigued. Rigormortis State of Muscle rigidity – Lack of ATP Determine Time of Death —Rigor Mortis Stiffening of the skeletal muscles after death At death, skeletal muscles cannot relax. Without oxygen, calcium accumulates in these muscles. – Calcium is used by the body to signal muscle contraction, this accumulation signals the muscles to contract. The muscles become stiff. Rigor mortis starts in the head and works 60 its way down to the legs. Determine Time of Death —Rigor Mortis 2 -6 hours postmortem (after death), rigor begins in the head 12 hours postmortem, rigor is complete and throughout the entire body 15 -36 hours postmortem, the muscle fibers begin to dissolve, and softening begins (rigor mortis starts to end). 36 -48 hours postmortem, rigor ends and is relaxed throughout the entire body. 61 Determine Time of Death —Rigor Mortis 2 -6 hours postmortem (after death), rigor begins in the head 12 hours postmortem, rigor is complete and throughout the entire body 15 -36 hours postmortem, the muscle fibers begin to dissolve, and softening begins (rigor mortis starts to end). 36 -48 hours postmortem, rigor ends and is relaxed throughout the entire body. 62 Study questions 1. Sources of ATP 2. Rigormortis 3.Role of calcium in muscle contraction 4.Biochemical events of muscle contraction