Cell Membrane L1 PDF

P r e s e n t a t io n b y : D r T e m b a M u d a r ik i Cell M e m br a ne M o le c u la r M e d ic in e X Y 3121 20 24  Learning Outcomes Cell Membrane Structure and Function: Gain a comprehensive understanding of the composition and architecture of cel...

P r e s e n t a t io n b y : D r T e m b a M u d a r ik i Cell M e m br a ne M o le c u la r M e d ic in e X Y 3121 20 24  Learning Outcomes Cell Membrane Structure and Function: Gain a comprehensive understanding of the composition and architecture of cell membranes, particularly the role of phospholipids. Analyse the effects of physical trauma on the integrity and selective permeability of cell membranes. Understand the interplay between the cell membrane and cytoskeleton in maintaining cellular structure under stress. Membrane Damage and Cellular Responses: Evaluate the consequences of direct trauma on membrane proteins and their functionalities. Investigate the cellular responses to membrane damage, including the biochemical pathways leading to inflammation and apoptosis. Mitochondrial Dynamics and Cellular Metabolism: Understand the structural organization of mitochondria and their significance in cellular metabolism. Discuss the implications of ischemia and reperfusion on mitochondrial function and the generation of reactive oxygen species. Inflammatory Response and Immune Activation: Explore the activation and role of the immune system in response to cellular and tissue injury. Examine the process of inflammation, including the recruitment of immune cells and the release of inflammatory mediators.  Learning Outcomes Muscle and Cardiomyocyte Structure and Pathophysiology: Describe the structural organization of skeletal and cardiac muscles and their excitation-contraction coupling mechanisms. Investigate the pathophysiological mechanisms underlying muscle and myocardial injuries. Clinical Implications of Tissue Injury and Repair: Analyse clinical cases related to muscle and myocardial injuries, including the processes of tissue repair and regeneration. Discuss the potential complications that may arise from persistent inflammation and ineffective repair, such as fibrosis and heart failure. Disease Processes and Treatment Strategies: Understand the pathophysiology of conditions such as rhabdomyolysis, myocardial infarction, and the development of arrhythmias. Explore the molecular mechanisms involved in post-injury repair, the limitations of tissue regeneration, and the potential for therapeutic intervention.  Overview A. I ntroduction B. M olecular M echanism of C ell M embrane Disr uption C. Signalling C ascade in M uscle I njury D. Skeletal M uscle I njury E. C ardiac M uscle I njury F. C linical C ase Presentations  Introduction Objectives:  The cell membrane is a dynamic and complex structure 1. Membrane Composition: Explore the molecular that is critical to the life of a cell. architecture of the cell membrane, including phospholipids  It acts as the boundary between the cell's internal and membrane proteins. environment and the outside world. 2. Physical Properties: Understand the fluid nature of the  Composed mainly of a phospholipid bilayer with membrane, how it maintains integrity, and the role of the embedded proteins, it controls what enters and exits the cytoskeleton in maintaining its structure. cell. 3. Trauma Response: Learn how physical trauma can disrupt  The membrane's integrity is vital for cellular membrane structure, affecting cell function and viability. homeostasis, signalling, and energy production. 4. Cellular Consequences: Discuss the downstream effects of membrane damage, including impacts on mitochondrial function, inflammation, and tissue repair. Components and Structure Proteins are involved in cell recognition, signal reception and transport across the membrane The Plasma Membrane Effects of Direct Trauma on Membrane Lipids Phospholipid structure review: hydrophilic head, hydrophobic tails In bilayer, tails packed tightly together via Van der Waals forces Choline/phosphate head groups on outside, tails interacting in middle Lipid fluidity allows membrane to remain flexible yet maintain integrity Effects on Membrane Lipid Organisation Direct trauma via shear/compression disrupts tight packing of lipid tails Physical force breaks non-covalent interactions between neighbouring tails Laterally separated lipids no longer tightly packed in bilayer structure Creates localized openings/defects in membrane through which cytosol leaks Loss of selective permeability and cellular contents/ions escape out  Effects on Membrane Integral Proteins Integral protein structure: transmembrane domains embedded in bilayer Hydrophobic interactions anchor protein tertiary structure within membrane Direct impact distorts protein conformations Shearing force unseats transmembrane helices from bilayer Detaches peripheral domains on inside/outside of cell Alters protein function such as transport, signalling etc Contributes to further loss of structural integrity Effects on Membrane-Cytoskeleton Interactions Focal adhesions contain integrin heterodimers that span membrane Integrin cytoplasmic domains connect to actin fibers via adapter proteins Forces applied parallel to membrane put strain on these integrin complexes  Increased Lateral Pressure on Membrane Actin cytoskeleton transmits force across integrins to pull on membrane Stretches phospholipid bilayer beyond a tolerable thinning pressure Toxicology Letters 100–101 (1998) 451–458 Laterally compressed lipids can no longer pack tightly in bilayer Detachment of Cytoskeleton from Membrane Strong perpendicular strain exceeded integrin-actin binding strength Detaches entire cytoskeletal scaffold from focal adhesions Alters lipid fluidity and diffusion as constraints are removed Modifies membrane curvature and cellular mechanotransduction Mitochondrial Structure and Function Inner/outer mitochondrial membranes enclose cristae and matrix Cristae are folds that house the electron transport chain complexes Ischemia Halts ATP Production Loss of blood flow cuts off O2 as final electron acceptor Inhibits cytochrome c oxidase, electron transport grinds to halt Stops ATP synthesis via oxidative phosphorylation Calcium Overload During Ischemia No ATP to power Na+/K+ ATPase and Ca2+ ATPase Intracellular and mitochondrial Ca2+ concentrations climb sharply  Reactive Oxygen Species Burst Reperfusion reintroduces O2 leading to xanthine oxidase pathway Damaged electron carriers in ETC leak electrons to O2 forming O2- and H2O2 Mitochondrial Permeability Transition High Ca2+ triggers opening of mitochondrial permeability transition pores Collapses proton gradient and membrane potential across inner membrane Cytochrome C Release Loss of inner membrane integrity liberates soluble proteins like cytochrome c Exits mitochondria and triggers caspase cascade of apoptosis Activation of Complement System & Increased Vascular Permeability Cell membrane damage exposes cellular antigens and phospholipids Binds and activates C1q component of complement classical pathway Anaphylatoxins C3a and C5a are cleavage products that bind endothelial cells Stimulate contraction of actin cytoskeleton and widening of junctions Neutrophil Recruitment & Pro-Inflammatory Mediator Release Chemokines and cytokines released induce expression of selectins and integrins Mediate tethering and rolling of neutrophils along vascular endothelium Firm adhesion and transmigration into injured tissue site Neutrophils, macrophages secrete TNFα, IL-1β, IL-6 and ROS to amplify response Skeletal Muscle Structure, Excitation-Contraction Coupling & Muscle Tear Pathophysiology  Striated muscle cells surrounded by basal lamina, connective tissue sheath  Multinucleated myofibers formed by fusion of myoblasts  Neuromuscular junction depolarization triggers inward calcium current  Calcium binds troponin C exposing binding sites on actin for myosin cross- bridges  Direct blunt force or eccentric contraction stretches sarcomeres beyond limit  Ruptures Z-disks, pulls apart actin-myosin filaments  Mechanisms of Rhabdomyolysis Prolonged ischemia exhausts energy stores and Na+/K+ ATPase function Sarcoplasmic calcium accumulation triggers proteolysis of contractile proteins  Clinical Case of Quadriceps Tear 28M presents acute left thigh pain after rugby tackle Unable to fully extend knee, crepitus on exam MRI shows partial tear of distal quadriceps tendon  Clinical Case of Quadriceps Tear A 23-year old male presents with left thigh pain after a soccer injury On examination, the thigh is swollen and he cannot fully extend the knee Most Likely Diagnosis -Compartment Syndrome  Clinical Case of Medication Complication Female receives medication after heart attack. Over time she notices increased fatigue and leg swelling. Potential medication complication - Hepatotoxicity Inflammation and Membrane Repair, Satellite Cell Activation & Regeneration of Myofibers Damaged membranes activate kinin-kallikrein and complement pathways Neutrophils clear debris and release TGFβ/IGF to signal regeneration IGF/FGF stimulate quiescent satellite cells adjacent to basal lamina Proliferate, fuse and differentiate into new myofibers New myotubes elongated, aligned and fuse nuclei Reform motor endplates and restore excitation-contraction coupling Persistent Inflammation Complications & Clinical Case of Exertional Rhabdomyolysis Excessive TNFα/IL-1β cause fibrosis instead of muscle regeneration Transforming growth factor beta promotes collagen deposition 42F collapses after long run, tea-coloured urine on examination CK 100,000 U/L, acute kidney injury indicators like BUN elevated Membrane Disruption in Ca2+ Toxicity & Proteolytic Degradation of Muscle High intracellular Ca2+ activates phospholipases and proteases Hydrolyses phospholipids and denatures membrane proteins Calpains, cathepsins cleave cytoskeletal, contractile proteins Triggers oncosis and releases myoglobin and proteins into bloodstream Cardiomyocyte Structure & Excitation-Contraction Coupling  Branched, striated cells connected via intercalated discs  Higher mitochondria content due to aerobic metabolism  SA node pacemaker potential triggers action potentials in cardiomyocytes  Voltage gated L-type Ca2+ channels open, calcium enters cytoplasm Pathophysiology of Myocardial Infarction & Clinical Case of STEMI Coronary artery plaque rupture induces thrombosis and vessel occlusion Downstream ischemia and calcium/ROS mediated membrane damage 62M presents with crushing chest pain radiating to left arm EKG shows ST elevations in lateral leads, troponin highly elevated Most appropriate management – Cardiac resynchronisation therapy  Physiological Repair After MI, Limitations of Cardiomyocyte Regeneration & Arrhythmias After MI  Inflammation clears necrotic myocytes by phagocytosis  Fibroblasts deposit collagen scar in infarct zone  Post-mitotic cells, proliferation rare after early neonatal period  Repair by hypertrophy of surviving cardiomyocytes  Ischemia-induced connexin remodelling causes non-uniform repolarization  Substrate for re-entry circuits and lethal ventricular arrhythmias Heart Failure After MI & Molecular Basis of Cardiac Rupture Loss of contractile tissue leads to compensated dilation and hypertrophy Eventually dilated cardiomyopathy if defect too large Collagen turnover imbalance during repair weakens infarct zone Ruptured scar unable to withstand wall stress during contraction  Summary  Cell Membrane: The Interface of Cellular Integrity and Injury  Traumatic Impact and Ischemic Repercussions  Inflammatory Response and Cell Death Pathways in Muscle Injury  Muscle Injury: From Clinical Cases to Molecular Insights  Cardiac Muscle: Specialized Responses to Injury  Comparative Molecular Insights  Concluding Thoughts  Recommendation 1. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2015). Molecular Biology of the Cell (6th ed.). Garland Science. This textbook provides an in-depth overview of cell structure and function, including detailed information on the cell membrane and its role in disease and injury. 2. Cooper, G. M. (2000). The Cell: A Molecular Approach (2nd ed.). Sinauer Associates. Cooper’s text offers a clear explanation of cellular molecular mechanisms, with a focus on the biochemical processes underpinning cell membrane dynamics and cellular responses to trauma. 3. Lieber, R. L., & Ward, S. R. (2011). Skeletal Muscle Structure, Function, and Plasticity (3rd ed.). Lippincott Williams & Wilkins. This book explores skeletal muscle physiology, including mechanisms of injury and repair, providing a thorough backdrop for understanding musculoskeletal responses to trauma. 4. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. (2019). (11th ed.). Elsevier Health Sciences. This leading cardiology reference covers the fundamentals of cardiovascular disease, including detailed sections on the pathophysiology of myocardial infarction and heart muscle repair. 5. Kumar, V., Abbas, A. K., & Aster, J. C. (2020). Robbins and Cotran Pathologic Basis of Disease (10th ed.). Elsevier Health Sciences. This pathology textbook is essential for understanding the disease processes, including cellular injury, inflammation, and repair, and how these processes manifest in both muscle and cardiac pathologies. 6. Tidball, J. G. (2005). Inflammatory processes in muscle injury and repair. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 288(2), R345-R353. This review article provides insight into the inflammatory processes involved in muscle injury and repair, which is crucial for understanding the cellular response to trauma.  Thank You P re se n ta tion b y: D r Te m b a M u d a rik i M o le c u la r M e d ic in e X Y 3121 20 24