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Such cases require assisted ventilation, such as positiveairway pressure ventilation. In myasthenia gravis, the appearanceof symptoms is usually episodic, and treatment often involves animmunosuppressive drug such as corticosteroids, as well as a cholinesterase inhibitor (for example, neostigmine). Cholinesteraseinhibitors inhibit acetylcholinesterase, prolonging the half-life ofacetylcholine in the neuromuscular junction. In some cases, plasmapheresis may be used to remove autoantibodies or thymectomymay be performed.Regional distributionof muscle weakness95%60%30%10%Ptosis and weakness of smileare common early signs.Improvement afteredrophonium chloride.In early stages, patient may feel fine inthe morning but develops diplopia andspeech slurs later in the day.Patient with chin on chest cannot resistwhen physician pushes head back.Clinical Manifestations of Myasthenia Gravis In myasthenia gravis, an autoimmune disease, antibodies block or reduce the number of nicotinic acetylcholine receptors at the neuromuscular junction,resulting in muscle fatigability.
Diagnostic tests include the edrophonium test. Edrophonium chloride is acholinesterase inhibitor and thus increases acetylcholine at the neuromuscular junction. Administered intravenously, it will temporarily relieve symptoms of muscle weakness, including diplopia (double vision), inmyasthenia gravis.THE SLIDING FILAMENT THEORYThe sliding filament theory describes the processes that takeplace in the sarcomeres that account for skeletal muscle contraction. The sliding of the interdigitated, anchored thickand thin filaments is the basis of contraction (Fig.
3.14).The thick filaments of the sarcomeres are composed of theprotein myosin and are anchored to the M line; the thin fila-ments are composed of actin, tropomyosin, and troponin andare anchored to the Z line (Fig. 3.15). Within the thin filament,globular G-actin is polymerized to form an α-helical filament(F-actin). Actin has binding sites for myosin along the grooveof its helix; these sites are covered by the protein tropomyosin.Three forms of troponin are also incorporated at regular intervals (troponin C, troponin I, and troponin T).40The Nervous System and MuscleBasement membraneNucleiSatellitecellSarcolemmaMuscleSarcoplasmMuscle fiberTendonEndomysiumMuscle fasciclesPerimysiumEpimysiumIZMyofibrilAHMZThin filamentThick filamentCrossbridgeMyofilamentsISarcoZAmereHMTwo-dimensional schemaof myofilamentsThree-dimensionalarrangement shown belowZCrmy oss slev ofila ectioels me nsind nts shoica wi wted thin relamy tionofi shibri psl a oftFigure 3.11 Organization of Skeletal Muscle Skeletal muscle is composed of fascicles that are inturn comprised of multinucleated muscle fibers.
These fibers are composed of smaller myofibrils, whichcontain sarcomeres, the site at which sliding of actin and myosin filaments produces contraction. Theorganization of sarcomeres within the skeletal muscle produces its striated appearance. The Z line marksthe boundary between two sarcomeres.
The I band contains only the actin thin filaments, which extend fromthe Z line toward the center of the sarcomere. Myosin thick filaments are found in the dark A band. At theH zone, there is no overlap between actin and myosin. The M line is at the center of the sarcomere and isthe site at which the thick filaments are linked with each other.In the relaxed state, in which cytosolic Ca2+ concentration isextremely low (10−7 M), binding of myosin to actin is blockedbecause myosin binding sites on actin are covered by tropomyosin.
Partially hydrolyzed ATP (ADP) is bound to themyosin head groups (see Fig. 3.15). When an action potentialcauses release of Ca2+ from the sarcoplasmic reticulum, bindingof Ca2+ to troponin causes troponin to move into the grooveof the actin α-helix. This results in exposure of the myosinbinding sites, thus promoting the binding of the myosin headgroup to actin, forming a crossbridge. This binding is followed by a ratcheting action of the myosin head group, shortening the sarcomere as the actin and myosin slide past eachother. ADP and inorganic phosphate (Pi) are released.
Next,binding of ATP to the myosin head group causes detachmentof actin and myosin, after which ATP is partially hydrolyzedSkeletal muscle fibers can be categorized as fast twitchand slow twitch fibers, also known as white muscle andred muscle, respectively. Most muscles in the body are composed of a mixture of the two types, but individual motor unitscontain only one fiber type. The oxygen-binding protein myoglobin is found only in slow twitch fibers and is responsible forits red color. Fast twitch (white muscle) fibers utilize anaerobicglycolysis as an energy source and therefore are high in glycogencontent.
This type of muscle is utilized for rapid, powerfulmovements; ATPase activity is high and contraction speed ishigh, and resistance to fatigue is low. Slow twitch (red muscle)fibers utilize oxidative phosphorylation, and thus glycogencontent is low. Slow twitch fibers are used for activities requiring endurance. ATPase activity and contraction speed are low,and resistance to fatigue is high.Nerve and Muscle PhysiologyTransverse (T) tubuleTerminal cisternaeSegment of muscle fiber greatly enlarged toshow sarcoplasmic structures and inclusions41TriadSarcoplasmic reticulumZ bandI bandA bandMitochondriaNucleusGolgi apparatusMyofilamentsSarcoplasmGlycogenMyofibrilLipidCollagenous basement membraneSarcolemmaFigure 3.12 Sarcoplasmic Reticulum The sarcoplasmic reticulum is a complex network surroundingthe myofibrils and storing high concentrations of Ca2+, sequestered from the sarcoplasm.
The membrane ofthe sarcoplasmic reticulum contains Ca2+-ATPase, which is essential for this sequestration. The transversetubules are deep invaginations of the sarcolemma and form triads with the terminal cisternae of the sarcoplasmic reticulum. These transverse tubules conduct the action potential from the sarcolemma to the cisternae, causing release of Ca2+.by ATPase; this causes “recocking” of the head group. Ifcytosolic Ca2+ is still elevated, myosin rapidly binds to actin,and crossbridge cycling in this manner causes the contractionto continue. Crossbridge cycling occurs simultaneously atmultiple sites, producing the shortening of the sarcomere.When Ca2+ is resequestered into the sarcoplasmic reticulum,muscle relaxes due to low cytosolic Ca2+ concentration.During crossbridge cycling, each cycle requires one ATP molecule to dissociate each myosin head group.
Furthermore,relaxation requires ATP, for sequestration of Ca2+ into thesarcoplasmic reticulum. In rigor mortis, because ATP isdepleted, myosin remains bound to actin, causing stiffness ofthe muscles.MECHANICAL CONSIDERATIONS IN SKELETALMUSCLE CONTRACTIONGeneration of force by skeletal muscle is controlled by anumber of factors (Fig. 3.16).
For example, variation in thesize of motor units is consistent with the function of themotor units. Small motor units are effective in performingfine movements, as in movements of the fingers and eyes,whereas large motor units perform coarser movements (seeFig. 3.16A). The force of contraction of skeletal muscles canbe increased by recruitment of motor units and summationof twitches. As noted earlier, all of the muscle fibers associatedwith a single motor unit will contract simultaneously.
Greatercontraction can be achieved by recruiting more motor units(spatial summation). With repeated stimulation of a muscle,temporal summation may occur. In this case, individualtwitches of the muscle occur without full relaxation betweentwitches, with greater force of contraction resulting as Ca2+ isreleased from the sarcoplasmic reticulum at a higher rate thanit can be resequestered between the twitches (see Fig. 3.16B).In tetanus (tetany), there is a sustained, forceful contractiondue to high frequency stimulation.Finally, the muscle tension generated during contraction isdependent on the resting tension or the degree of stretch ofthe muscle at rest. In other words, there is a length–tension42The Nervous System and MuscleThin filamentElectric impulseSarcolemmaⴙⴚⴙⴚⴙⴚⴙⴚSarcoplasmⴙTerminal cistern ofsarcoplasmic reticulumKⴙⴚⴙⴚⴙExtrudedCa2Ca2ⴙCa2ⴙCa2ⴙⴙⴚⴚⴙⴚⴙⴙⴙⴚⴚⴚCa2ⴙⴙⴚTransverse (T) tubuleⴚTerminal cistern ofsarcoplasmic reticulumⴚSarcoplasmicreticulumZ bandⴚNaⴚCrossbridgesThick filamentⴚⴚⴚⴚⴚⴙⴙⴙⴙⴙⴙNaCa2ⴙⴚⴙCa2ⴙⴙⴙⴙⴙⴚⴚⴚⴚⴚⴚⴚⴙⴙⴙCa2ⴙCa2ⴙⴚKⴙⴙⴚⴙⴚCa2ⴙElectric impulse traveling along muscle cell membrane (sarcolemma) from motor endplate (neuromuscularjunction) and then along transverse tubules affects sarcoplasmic reticulum, causing extrusion of Ca2 toinitiate contraction by “rowing” action of crossbridges, sliding filaments past one another.Figure 3.13 Excitation-Contraction Coupling When an action potential in a motor neuron resultsin the release of acetylcholine at the neuromuscular junction, binding of acetylcholine on the sarcolemmaopens a cation channel, permitting influx of Na+.
An action potential is produced and spreads into thetransverse tubules, resulting in the release of Ca2+ stored in the sarcoplasmic reticulum, initiating crossbridgeformation and muscle contraction. Ca2+ is resequestered into the sarcoplasmic reticulum by Ca2+-ATPaseto terminate the contraction.relationship for skeletal muscle (see Fig.
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