MPP block 2 lecture 1.pdf

1.Reproduce the hierarchical structure of skeletal muscle. Myosin main body: two heavy chains Myosin Head: ATPase activity and contains the actin-interaction site, undergoes a conformational change (power stroke) that pulls the actin filament, generating the force needed for contraction. Neck: act...

1.Reproduce the hierarchical structure of skeletal muscle. Myosin main body: two heavy chains Myosin Head: ATPase activity and contains the actin-interaction site, undergoes a conformational change (power stroke) that pulls the actin filament, generating the force needed for contraction. Neck: acts as a flexible hinge between the head and tail. also provides an attachment site for light chains (regulatory and essential light chains), which are involved in modulating the activity of the myosin head. Tail: consists of two long heavy chains (anchor) that form a coiled-coil structure, enabling myosin molecules to dimerize and form thick filaments.These thick filaments align in parallel within the sarcomere, with the heads facing outward to interact with actin. G-actin forms the building blocks of F-actin, and two F-actin strands make up the structural core of the thin filament. Tropomyosin: A long, rope-like protein that winds along the groove of the F-actin double helix. Tropomyosin blocks the myosin-binding sites on actin when the muscle is relaxed, preventing contraction. Troponin: A complex of three proteins (Troponin C, Troponin I, and Troponin T) that regulate the interaction between actin and myosin. When calcium binds to Troponin C, it causes a conformational change in the troponin complex, which shifts tropomyosin away from the myosin-binding sites on actin, allowing muscle contraction to occur. Troponin C: Calcium sensing Troponin I: inhibit actin/myosin interaction Troponin T: tethers troponin to tropomyosin Relationship of Myosin and Actin: thick filaments of myosin are surrounded by thin actin filaments Functional unit of the skeletal muscle: sarcomere ​Sarcomere: defined between two Z disks and made up of numerous cytoskeletal proteins that constrain the thick and thin filaments to aid in its assembly and maintenance Z disk: proteinaceous plates that anchor thin filaments Crossbridge: Region of overlap between the two types of filament, forming distinct banding patterns α- Actinin: Binds the ends of thin filaments to the Z disks Titin: Forms a spring one end is attached to a Z disk, the other to the thick filaments, that limits how much the sarcomere can be stretched. also centers the thick filaments within sarcomere Dystrophin: Anchors both thin and thick ends to the cytoskeleton and surface membrane, aligns the Z disk with disks in adjacent myofibrils and muscle fibers Sarcoplasm: cytoplasm of muscle cells, high Mg2+, phosphates, and myoglobin, dense with mitochondria for ATP supply T-Tubule: Carry action potentials from cell surface to structures responsible for Ca++ release Terminal Cisternae: Site of specialized sensors and ion channels for E-C coupling, location of RyR that is opened by DHP receptors Sarcoplasmic Reticulum: contains Ca2+ and terminal cisterna, SERCA pumps Ca2+ back in during repolarization 2.Explain the organization and compare and contrast the functions of myosin and actin. 3.Relate the clinical presentation of a disease to the importance of these skeletal elements to the function of the sarcoplasm & sarcomere. Duchenne muscular dystrophy - Results from a recessive X-linked mutation in the dystrophin gene - Loss of dystrophin function prevents the cytoskeleton from attaching to the sarcolemma and the muscle fiber becomes necrotic, causing muscle wasting myasthenia gravis (MG) - Autoimmune condition, most common disorder affecting neuromuscular transmission - Antibodies against nicotinic acetylcholine receptors interfere with normal signaling at NMJ 4.Diagram the neuromuscular junction, list the steps of excitation, and characterize the important ions driving action potentials in skeletal muscle. Relate the clinical presentation of a disease to the importance of NMJ function. Neuromuscular Junction (NMJ) Diagram: The neuromuscular junction consists of: 1. Motor neuron terminal with synaptic vesicles containing acetylcholine (ACh). 2. Synaptic cleft, a small gap between the neuron and the muscle. 3. Motor endplate, a specialized region of the skeletal muscle membrane (sarcolemma) with ACh receptors. Steps of Excitation at the NMJ: 1. Action potential arrival at the motor neuron terminal. 2. Voltage-gated calcium channels open, allowing calcium ions (Ca²⁺) to enter the neuron. 3. Synaptic vesicles release acetylcholine (ACh) into the synaptic cleft via exocytosis. 4. ACh binds to nicotinic receptors on the muscle's motor endplate. 5. Ligand-gated sodium channels open, causing Na⁺ influx into the muscle cell. 6. Depolarization of the sarcolemma triggers an action potential, which propagates along the muscle membrane. 7. The action potential travels down the T-tubules, activating voltage-sensitive dihydropyridine receptors (DHPR).  8. DHPR mechanically interacts with ryanodine receptors (RyR) on the sarcoplasmic reticulum, releasing calcium ions (Ca²⁺). 9. Ca²⁺ binds to troponin, allowing the cross-bridge cycle and muscle contraction to proceed. Important Ions Driving Action Potentials in Skeletal Muscle: 1. Sodium (Na⁺): Influx causes depolarization of the muscle membrane. 2. Potassium (K⁺): Efflux leads to repolarization, restoring the resting membrane potential. 3. Calcium (Ca²⁺): Essential for triggering vesicle fusion at the neuron terminal and for muscle contraction via troponin binding. Disease Example: Myasthenia Gravis (MG) Myasthenia Gravis is an autoimmune disorder where antibodies attack ACh receptors at the NMJ. This reduces the number of functional receptors, impairing signal transmission. Clinical Presentation: Muscle weakness that worsens with activity, ptosis (drooping eyelids), and difficulty swallowing or breathing. Relevance to NMJ Function: Reduced ACh receptor availability means fewer Na⁺ channels open, leading to inadequate depolarization and action potential generation. This impairs muscle contraction, explaining the weakness and fatigue in patients with MG. 5.Define the role of each “key player” in excitation-contraction coupling. In excitation-contraction coupling (ECC), several key players ensure the link between the action potential (excitation) and muscle contraction. Below are the roles of each important component: 1. Acetylcholine (ACh) Role: Neurotransmitter released from the motor neuron at the neuromuscular junction. ACh binds to nicotinic receptors on the motor endplate of the muscle fiber, initiating depolarization. 2. Nicotinic Acetylcholine Receptors (nAChRs)  Role: Ligand-gated ion channels located on the motor endplate. When ACh binds to these receptors, they open, allowing sodium ions (Na⁺) to enter the muscle fiber, initiating an action potential in the sarcolemma. 3. Sodium (Na⁺) Ions Role: Na⁺ influx through nAChRs causes the initial depolarization of the sarcolemma, which triggers the action potential along the muscle fiber membrane. 4. Voltage-Gated Sodium Channels Role: Located on the sarcolemma and T-tubules, these channels amplify the depolarization, enabling the action potential to propagate rapidly throughout the muscle fiber. 5. T-Tubules (Transverse Tubules) Role: Invaginations of the sarcolemma that conduct the action potential deep into the muscle fiber, ensuring synchronous activation of contraction throughout the muscle. 6. Dihydropyridine Receptors (DHPR) Role: Voltage-sensitive receptors located on the T-tubules. They detect the action potential traveling along the T-tubules and undergo a conformational change, interacting with ryanodine receptors. 7. Ryanodine Receptors (RyR) Role: Located on the sarcoplasmic reticulum (SR), these channels release calcium ions (Ca²⁺) into the cytosol of the muscle fiber when activated by the DHPR. 8. Calcium Ions (Ca²⁺) Role: Released from the sarcoplasmic reticulum, Ca²⁺ binds to troponin C on the actin filaments, initiating the cross-bridge cycle by shifting tropomyosin to expose binding sites for myosin on actin. 9. Troponin Complex Role: Composed of three subunits: ○ Troponin C (TnC): Binds Ca²⁺ and undergoes a conformational change. ○ Troponin I (TnI): Inhibits actin-myosin interaction in the absence of Ca²⁺. ○ Troponin T (TnT): Attaches to tropomyosin and helps in the regulation of contraction.  When Ca²⁺ binds to TnC, the troponin complex shifts tropomyosin away from the actin binding sites, allowing myosin to bind to actin. 10. Tropomyosin Role: A regulatory protein that blocks the myosin-binding sites on actin filaments when the muscle is relaxed. Ca²⁺ binding to troponin moves tropomyosin out of the way, allowing actin-myosin interaction for contraction. 11. Myosin Role: A motor protein that binds to actin filaments and generates force for contraction through the cross-bridge cycle. Myosin heads use ATP to power their movement along actin, producing the muscle contraction. 12. Sarcoplasmic Reticulum (SR) Role: The intracellular calcium store. During relaxation, Ca²⁺ is pumped back into the SR by the SERCA (sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase) pump, lowering cytosolic Ca²⁺ levels and ending muscle contraction. 6.Diagram cross-bridge cycling and contraction of the sarcomere. Cross-Bridge Cycling: 1. Resting State (No Ca²⁺): ○ Tropomyosin covers the myosin-binding sites on actin, preventing cross-bridge formation. ○ Myosin heads are in an energized state, holding ADP and inorganic phosphate (Pi). 2. Calcium Release (Initiation): ○ Ca²⁺ binds to troponin C (TnC), causing a conformational shift in the troponin-tropomyosin complex, exposing myosin-binding sites on actin. 3. Cross-Bridge Formation: ○ Myosin head binds to exposed actin sites, forming the cross-bridge. 4. Power Stroke: ○ Once bound, the myosin head undergoes a conformational change, releasing ADP and Pi, and pulling the actin filament toward the center of the sarcomere. This is called the power stroke, which shortens the sarcomere. 5. Cross-Bridge Detachment: ○ ATP binds to the myosin head, causing it to detach from actin.  6. Reactivation of Myosin (Reset): ○ ATP is hydrolyzed to ADP and Pi, re-cocking the myosin head into its high-energy state, ready for another cycle. 7. Cycle Continuation: ○ As long as Ca²⁺ and ATP are available, the cross-bridge cycle continues, driving sarcomere shortening and muscle contraction. Sarcomere Contraction: Sarcomere: The fundamental unit of muscle contraction. During contraction: ○ Z-lines move closer together. ○ I-band (light zone with only actin) shortens. ○ H-zone (region with only myosin) disappears as actin and myosin filaments overlap. ○ A-band (length of the myosin filament) remains constant. Key Components of the Sarcomere: 1. Z-line: Defines the boundary of the sarcomere. 2. Actin: Thin filament anchored to the Z-line. 3. Myosin: Thick filament in the center, with heads that interact with actin. 4. Tropomyosin: Covers actin's myosin-binding sites at rest. 5. Troponin: Regulates the position of tropomyosin. When you draw the diagram: Include the sarcomere structure (Z-line, actin, myosin, A-band, I-band, H-zone). Illustrate the steps of the cross-bridge cycle (attachment, power stroke, detachment, reactivation). Show calcium interacting with troponin and the shift of tropomyosin. 7.Summarize the principle of preload and relate it to the sarcomere, thin filaments, and thick filaments.