L2 Muscle Contraction 2024 PDF

BIOCHEMISTRY MUSCLE CONTRACTION lecture 2 DR. MARIATI ABDUL RAHMAN Center of Craniofacial Diagnostics and Biosciences References 1. Medical Biochemistry 2nd edition, Baynes J.W. and Dominiczak M.H. Elsevier Mosby 2005 2. Fundamentals of Anatomy & Physiolo...

BIOCHEMISTRY MUSCLE CONTRACTION lecture 2 DR. MARIATI ABDUL RAHMAN Center of Craniofacial Diagnostics and Biosciences References 1. Medical Biochemistry 2nd edition, Baynes J.W. and Dominiczak M.H. Elsevier Mosby 2005 2. Fundamentals of Anatomy & Physiology, 7th edition. Martini F.H. Pearson 2006 3. Harper’s Biochemistry, Murray R.K., Granner D.K., Mayes P.A. & Rodwell V.W. 23rd edition. Appeton & Lange 1993. Objectives: Able to Describe the mechanism of muscle contraction. Describe the regulation of muscle contraction. Identify the source of energy for muscle contraction.  Muscle contraction It is a process leading to shortening of muscle tissue & development of tension. Consists of cyclic attachment and detachment of globular head portion of myosin to the F-actin filament. ‘The sliding filament model’ The sliding of the thin filaments within the interspaces of the thick filaments- the total length of fibers shortened. The length of sarcomere decreases but the length of individual filaments did not change. Biochemical cycle of muscle contraction ATP hydrolysis produces macroscopic movement. How? Cyclic attachment and detachment of myosin to F-actin filament. Followed by a change of actin-myosin interaction, they slide past one another. Energy is supplied by ATP. ATP hydrolysis is accelerated by binding of myosin head to F-actin. 5 Mechanism of skeletal muscle contraction- 5 steps 1. In relaxation phase of muscle contraction, myosin head alone can hydrolyze ATP to ADP + Pi, but product is not released. 1. The ADP + Pi-myosin complex is energized & in high energy conformation. 2. Binding of myosin to actin is inhibited by tropomyosin which blocks the myosin binding site on actin at low calcium concentration.  Sarcoplasmic reticulum regulates intracellular levels of Ca2+ in skeletal muscle. In resting muscle sarcoplasm, [Ca2+] is 10-7- 10-8mol/L. This state is achieved because Ca2+ is pumped into sarcoplasmic reticulum through active transport system- Ca2+ Sarcoplasm- cytoplasm of striated muscle fibre. ATPase, initiating relaxation. 2. When muscle is stimulated, signals carried out by the nerve cell (motor neuron) causes a change in voltage potential across the cell membrane. Also affect the voltage- dependent Ca2+ channel.  5 steps (continues) 2. When muscle is stimulated, calcium enters the sarcoplasm (cytoplasm of the muscle fibre) through voltage-gated calcium channels. Ca2+ binding to Tn-C causes conformational change in Tn-I, which is transmitted through Tn-T to Tropomyosin. Movement of tropomyosin exposes the myosin-binding site. Myosin head with ADP+Pi can rotate freely will find F-actin, making an angle of 90º with fiber axis.  5 steps (continues) 3. This interaction forms actin- myosin-ADP-Pi complex (cross bridge formation). Formation of this complex promotes release of ADP + Pi. Because conformation of lowest energy is 45 º, myosin changes its angle from 90 º to 45 º by pulling the actin towards center of sarcomere – Power stroke. Actin moves about 10nm, increasing their overlap and causing muscle to contract.  5 steps (continues) 4. New ATP molecule binds to myosin-F actin complex. Myosin- ATP has poor affinity towards actin, thus myosin (ATP) head is 5 released. 5. Relaxation- ATP is hydrolyzed again but ADP+Pi is not released. The stage is now ready for continued muscle contraction in response to the next surge of Ca2+ in the sarcoplasm. # It should be clear that ATP dissociates myosin head from thin filament and powers the contraction. Efficiency of this contraction is about 50%. Muscle relaxation Relaxation occurs when: 1. Sarcoplasmic Ca2+ falls below 10-7 mol/L by action of Ca2+ATPase 2. TpC.4Ca2+ loses its Ca2+. 3. Troponin, via interaction with with tropomyosin, inhibits further myosin-head-F- actin interaction.  A decrease of ATP in sarcoplasm (e.g by excessive usage during the cycle of contraction- relaxation or by diminished formation) has 2 major effects 1. The Ca2+ATPase (Ca2+ pump) ceased to maintain the low conc of Ca2+, thus interaction of myosin head –F-actin is promoted. 2. The ATP-dependent detachment of myosin heads from F-actin cannot occur, and rigidity sets in. The condition of rigor mortis, followed by death. -Stiffening of the body after death Components involved in the power stroke process.  Sliding filament theory When skeletal muscle fiber contracts, 1. H zones and I band get smaller. 2. Zones of overlap get larger. 3. Z lines moves closer together 4. Width of band A remains constant These observations make sense only if thin filaments are sliding toward the center of each sarcomere, alongside thick filaments. Regulation of muscle contraction In all systems, Ca2+ plays a key regulatory role. 2 general mechanisms of regulation: 1. Myosin-based. Myosin linked regulation involves both small subunits of myosin, the regulatory and the essential light chains. This type of regulation is widely distributed in invertebrates, and a variant of it operates also in the smooth muscles of vertebrates. E.g light chain is phosphorylated then the muscle can contract. 2. Actin- based (next slide)  Regulation of muscle contraction 2. Actin based regulation. Occurs in vertebrate skeletal and cardiac muscles, both striated. Potentially limiting factor- ATP. At rest, skeletal muscle system is inhibited by troponin system. All 3 components are bound to F-actin- tropomyosin complex. TpI prevents the binding of myosin head to its F-actin attachment side either by altering conformation of F-actin via tropomyosin molecules or simply rolling tropomyosin to a position that blocks the active site. This is the inhibited state of relaxed striated muscle. Cardiac Muscle Striated like skeletal muscle. Contracts rhythmically under involuntary control. General mechanism of contraction is similar to that in skeletal muscle but sarcoplasmic reticulum is less organised. Transverse tubule network (extension of plasma membrane) is more developed. Therefore the heart is more dependent/ requires extracellular calcium for contraction. Contraction occurs without neural stimulation - automaticity  Cardiac Muscle Timing of contraction is normally determined by specialized cardiac muscle cells called pacemaker cells. Cardiac muscle cell contractions last roughly 10 times longer than those from the skeletal muscle fibers. More responsive towards hormonal regulation – e.g cAMP-dependent protein kinases phosphorylate transport proteins &TnI, mediating changes in the response of contraction in response to epinephrine.  Smooth muscle Non- striated Thick filaments are scattered throughout the sarcoplasm of smooth muscle cell. Myosin protein are organized differently. Contains -actinin & tropomyosin but not troponin. Light chains of smooth muscle differ from striated muscle myosin. Contraction regulated by Ca 2+ Phosphorylation of myosin p- light chains initiates contraction of smooth muscle.  Sources of energy for muscle contraction 1. Glycolysis, using blood glucose or muscle glycogen 2. Oxidative phosphorylation – synthesis of ATP 3. Creatine phosphate 4. From 2 molecules of ADP in a reaction catalyzed by adenylate kinase. Multiple source of ATP in the muscle.  Multiple source of ATP in the muscle. 1. In sarcoplasm of skeletal muscle – a large storage of glycogen in granules close to I band. Release of glucose depends on a specific muscle glycogen phosphorylase which can be activated by Ca2+, epinephrine and AMP. Ca2+ initiates muscle contraction and activates pathway to provide energy.  Multiple source of ATP in the muscle. Under aerobic condition, muscle can generate ATP by oxidative phosphorylation. Multiple source of ATP in the muscle. 2. Creatine phosphokinase. - muscle specific enzyme ADP + CP → ATP + creatine During contraction, each myosin head breaks down ATP, producing ADP and Pi. Energy stored in CP is used to recharged ADP, converting it back to ATP through reverse reaction. Enz: creatine phosphokinase (CPK/CK).  CPK-Dimer proteins with 2 subunits M & B CPK has 3 isoforms; differs in subunit composition CK1 -BB – brain CK2 - MB–cardiac tissue CK3 - MM – skeletal muscle. When muscle is damaged, CPK will leak out into the blood. High [CPK] – indicates serious muscle damage. ATP and CP reserves. 1 muscle fibre – may contain 15billion filaments. Each thick filament breaks down roughly 2500 ATP/sec. Enormous demand of ATP. Resting muscle fibre contains only enough ATP & other high energy compound to sustain contraction until additional ATP can be generated. ATP and CP reserves. At rest, ATP transfers energy to creatine. Creatine – small molecule, assemble from arginine and glycine. Energy transfer creates another high energy compound – creatine phosphate (CP). 3. Adenylate kinase - Catalyzes formation of one ATP and AMP from 2 ADP. - This reaction is coupled with the hydrolysis of ATP by myosin ATPase during muscle contraction. 2ADP ↔ ATP + AMP Energy Utilised Initial Duration of stored through quantity isometric tetanic contraction as supported by each energy source alone. ATP ATP→ADP + 3mmol 2 sec Pi CP ADP + CP 20mmol 15sec →ATP + C Glycogen Glycolysis 100mmol 130sec Aerobic metab. 2400sec Isometric- denoting muscular action in which tension is developed without contraction of the muscle. Muscle disorders: Muscular Dystrophy. X-linked hereditary degenerative myopathies Characterized by muscle weakness without the involvement of nervous system. E.g.: Duchenne muscular dystrophy & Becker muscular dystrophy Loss of individual muscle fibres leading to disruption in fibre management, degeneration and fibrosis of the tissue.  Variables DMD BMD Onset 3-5 years 5-15 years Life Teens 30-40’s expectancy Mental Common Uncommon retardation Dystrophin Dystrophin Western is markedly level is blot reduced/ common but absent protein is abnormal.  Duchenne muscular dystrophy. 20fold elevation of serum CPK. Lack of dystrophin in muscle. Dystrophin reinforces plasma membrane of muscle cells & mediates interaction with extracellular matrix. In its absence, plasma membrane is damaged during contraction – muscle death. The signs of Duchenne muscular dystrophy may not be noticed until ages 3 to 7, when the young boy is likely to start having difficulty walking. (Because of the way it is inherited, only boys usually have Duchenne muscular dystrophy.) Another characteristic sign is that the calf muscles, although becoming weaker, are enlarged partly because of accumulating deposits of fat in them.  Muscle weakness steadily advances from the lower to the upper body, and a wheelchair is usually needed by about age 12. Complications such as scoliosis (side-to-side curving of the spine) and lung infections commonly occur in the teen years, and the person may not live past his late teens or early twenties. Death by the age of 20 from respiratory and cardiac failure. Becker muscular dystrophy. Milder symptoms Altered dystrophin proteins. Survived until 40yrs old No treatment. Animal trial – injection of satelite cell (that produces dystrophin & incorporate into skeletal muscle) has shown some promises.