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Year 1 Revision – Tricky Limbs and Back T opics Omar SalimILOs • Calcium metabolism • Healing of tendons/bones • Muscle physiology • MSK embryology • Some embryology Qs to test your knowledge!Calcium Metabolism • Calcium - nerve conduction, 2nd messenger, cardiac & skeletal muscle contractility, ion channels, enzymes, bones & teeth, clotting • 99% in bones and 1% soluble in cells & plasma (dynamic equilibrium) • 45% physiologically active (free ions), 55% bound to albumin • 2 important hormones for maintaining calcium levels = PTH & vitamin D • PTH – from chief cells of parathyroids, hypocalcemia stimulates, 3 mechanisms to increase Ca 2+ levels: • Bone – increased osteoclasts, decreased osteoblasts à release Ca 2+from bone (resorption) 2+ • Kidney → stimulates Ca reabsorption, decreases phosphate reabsorption • Indirect – activates renal 1 alpha-hydroxylase (increasing production of active vitamin D i.e. 1,25(OH) D2/ calcitriol) • Calcitriol promotes absorption of calcium in small intestine • Results in increase in calcium & decrease in phosphateCalcium Metabolism • Vitamin D (Calcitriol) • Kidneys – increased reabsorption of calcium & decreased reabsorption of phosphate. • Bone – stimulates PTH which increases calcium reabsorption. • Small intestine – increased absorption of calcium and phosphate. • Increasing calcium and phosphate concentrations. • Calcitonin – parafollicular cells of thyroid, decreases calcium concentrations, stimulated by gastrin from small intestine when a lot of calcium is taken in by diet. • Decreases reabsorption of Ca and PO in kidneys • Decreased osteoclastic activityBone Fracture Healing • 2 types of bone healing – indirect (secondary) & direct (primary) • Indirect (secondary) fracture healing – via callus formation, differential tissue formation until skeletal continuity restored • Haematoma à inflammation à soft callus (2 weeks) à hard callus • Fibroblasts aggregate, revascularisation, collagen fibres & granulation tissue fill gap (osteoblasts & chondroblasts), calcified into woven bone • Remodelling of soft callus to hard lamellar bone by osteoblasts & osteoclasts strengthens bone along stress lines & shape returns • Direct fracture healing – ‘artificial’ surgical situation, direct formation of bone without callus formation • Fracture stable - no movement between 2 broken ends under physiological load, relies upon compression of bone ends • Cells able to bridge fracture gap, direct formation of bone via osteoclastic absorption and osteoblastic formationT endon Healing • 3 phases under action of cytokines & mediators (e.g. PDGF, TGFß) • Inflammation (0-7 days) – inflammatory cells migrate from epitendinous tissues (sheath, periosteum, soft tissues), epitenon (surrounding connective tissue) & endotenon (enclosing fibres carrying vessels, nerves) • Matrix proteins laid down as scaffolding for collagen synthesis • Repair (3-60 days) – fibroblasts/tenocytes migrate to zone of injury, begin collagen synthesis (by day 5) • Initially collagen type 3 in random orientation • In 4th week fibroblasts proliferate & take over healing process (synthesising & reabsorbing collagen) • ingrowth via collagen/fibronectin scaffolding)rientated along lines of force), vascular • Organisation (28-180 days) – final stability acquired by normal use of tendon • Cross linking between fibrils further increasing tendon tensile strength • Complete regeneration never achieved – defect remains hypercellular, thinner collagen fibrilsMuscle Physiology • 3 types of muscles – skeletal, smooth, cardiac • Skeletal muscle – striated, alternating light & dark protein bands, somatic motor neurons innervate • Muscle comprised of fibres arranged in bundles called fascicles • Fascia – sheet that lines muscle & holds muscle with similar functions together. 3 layers of connective tissue extend from fascia • Epimysium – encircles entire muscle • Perimysium – surrounds groups of 10-100 or more muscle fibres separating them into fascicles • Endomysium – surrounds each muscle fibreMuscle Physiology • Sarcolemma - plasma membrane of muscle cell • T-tubules – extensions of sarcolemma, tunnels running through muscle fibre from surface towards centre, many ion channels & pumps • Sarcoplasm – cytoplasm containing glycogen, myoglobin • Myoglobin – iron- & oxygen-binding protein, releases O2 when needed by mitochondria • Myofibrils - threads inside muscle fibre, cause contraction, striated • Sarcoplasmic reticulum - surrounds each myofibril, similar to smooth ER, stores Ca2+ in terminal cisternaeMuscle Physiology • Within myofibril are myofilaments containing contractile proteins: • Thin composed of actin • Thick composed of myosin • Arranged in compartments called sarcomeres. • Z-discs – separate one sarcomere from other • I Band – lighter area, just actin, contains Z-disc • A band – darker middle part, entire myosin length, includes actin & myosin crossover area, contains H zone • H zone – just myosin, gets bridged by contraction, contains M line • M line – middle of sarcomere, hold myosin filaments togetherMuscle Physiology • Thick myosin filaments have ‘heads’ • Thin filaments anchored to Z-discs, contain two proteins: • Tropomyosin blocks myosin from binding sites on actin. • Troponin reacts with calcium which opens these binding sites. • position of thick filament.n spanning from Z to M line, stabilises • Dystrophin links thin filaments to sarcolemmaMuscle Physiology Muscle excitation & contraction 1. ATP hydrolysis – myosin head includes ATP binding site & ATPase. ATP ➔ ADP+Pi. 2. Cross-bridge formation – attachment of myosin to actin 3. Power stroke – ADP released, cross-bridge rotates & moves thin filaments past thick filaments towards centre of sarcomere 4. Detachment of myosin from actin – cross-bridge remains attached until ATP binds, then myosin detachesMuscle Physiology Neuromuscular Junction 1. Release of acetylcholine – impulse along somatic motor neuron triggers voltage-gated Ca2+ channels to open, ACh vesicles fuse with plasma membrane & release ACh into synaptic cleft 2. Activation of ACh receptors – bind to motor end plate receptors, causes Na+ inflow 3. Production of muscle fibre action potential – depolarises muscle, action potential propagates along sarcolemma into T- tubules causing SR release of Ca2+ à thin filament sliding 4. Termination of ACh activity – broken down by acetylcholinesterase (AChE).Muscle PhysiologyMuscle PhysiologyMuscle Physiology Muscle metabolism • Muscle uses ATP to fuel • Cross Bridges (75%) • Ca Pumps (20%) • Na/K Pumps (5%) • Three ways to produce ATP 1. Creatine Phosphate 2. Anaerobic cellular respiration 3. Aerobic cellular respirationMuscle Physiology • Creatine Phosphate (CrP) – produced from leftover ATP when muscle relaxed • Fast (seconds), very short term replenishment of ATP • Doesn't require oxygen • Happens in sarcomere • Anaerobic Cellular Respiration – rapid (~1/2 minute) but inefficient resynthesis of ATP in sarcoplasm. • Glucose from blood catabolised to generate 2 ATP. Muscle Physiology • Aerobic Cellular Respiration – slower (several minutes) but maximally efficient (36 ATP) resynthesis by aerobic glycolysis in mitochondria. • Pyruvate from glycolysis converted to Acetyl CoA à enters mitochondria & is hydrolysed. • Oxygen from blood and from myoglobin. • Other slower methods: • Aerobic lipolysis – even slower aerobic metabolism of fats in mitochondria, main way glycogen stores replenished. • Aerobic protein breakdown – ultra slow metabolism of amino acids.Muscle Physiology • Motor unit = motor neuron & muscle fibres it supplies • Less fibres per unit for finer muscle control (e.g. eyes, fingers) vs more in larger (e.g. quadriceps) • 3 types of muscle fibre: • Type 1 (slow twitch oxidative, red) – small motor units, slow myosin, endurance, less powerful, use fats as fuel • Type 2A (fast twitch oxidative, red) – big motor units, fast myosin, powerful, similar peak force to IIb but take longer to reach • Type 2B/X ( fast twitch glycolytic, white) – big motor units, fast myosin, work only under anaerobic conditions, tire quickly, reach peak force quickest.Embryology • Gastrulation – during 3rd week, 3 germ layers develop from epiblast (bilaminar disc cells). • Ectoderm à epidermis, CNS, PNS, retina of eye, ear, nose etc. • Mesoderm à smooth muscular coats, striated muscles, skeleton, connective tissues, vessels, most of cardiovascular system, blood cells & bone marrow, reproductive & excretory organs. • Endoderm à epithelial linings of respiratory & GI tracts, including glands of associated organs (e.g. liver, pancreas)EmbryologyEmbryology Mesoderm • Notochord = midline structure that signals for patterning surrounding tissues • As notochord & neural tube form, intra-embryonic mesoderm on each side proliferates into column of paraxial mesoderm. • Each column is continuous laterally with intermediate mesoderm, which gradually thins into layer of lateral plate mesoderm. Lateral plate mesoderm continuous with extra-embryonic mesoderm that covers umbilical vesicle & amnion. Origin of Muscles • Skeletal Muscle – paraxial mesoderm • Smooth Muscle: • Gut & derivatives – visceral layer of lateral plate mesoderm • Pupil, mammary, sweat glands – ectoderm • Cardiac Muscle – visceral layer of lateral plate mesodermEmbryology Somite Formation – toward end of 3 week, paraxial mesoderm differentiates & begins to divide into paired cuboidal bodies called somites on each side of neural tube. • Form along craniocaudal axis with time – first pair arise in occipital region • Eventually 42-44 pairs of somites – 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 8-10 coccygeal. • Somitogenesis regulated by cyclic levels of NOTCH & WNT • NOTCH accumulates in presomitic mesoderm destined to form next somite, then decreases as somite established à diminishing gradient of NOTCH craniocaudally during somitogenesis • WNT highly expressed caudallyEmbryology Somite Differentiation – into sclerotomes or dermomyotomes • Sclerotome formation - by 4th week, cells in ventral & medial walls à form sclerotome (SHH, noggin trigger), which go on to form vertebrae & ribs • Dermomyotome formation - cells in dorsal half of somite à dermomyotome, which forms myotome (precursors for muscle cells) & dermatome (precursors for dermis) • Each myotome & dermatome retains innervation from its segment of origin (has own segmental nerve), no matter where cells migrate. Hence, each somite forms its own sclerotome (tendon & bone), its own myotome (segmental muscle), and it’s own dermatome (dermis of back). Molecular Regulation • SHH, noggin – sclerotome formation • PAX1 – sclerotome à vertebrae • PAX3 – demarcates dermatome • NT-3 – dermatome à dermis • MyoD & MYF5 – muscle differentiation, belong to myogenic regulatory factors (MRFs). • WNT – activates muscle differentiation via MyoD/MYF5 • BMP – inhibits muscle differentiation via MyoD/MYF5EmbryologyEmbryology Muscle Types Smooth Muscle – most originates from visceral mesoderm • Serum Response Factor (SRF) –responsible for smooth muscle differentiation • Myocardin & myocardin-related transcription factor (MRTFs) – enhance SRF activity Skeletal Muscle • Myogenesis starts with elongation of nuclei & cell bodies of mesenchymal stem cells as they differentiate into myoblasts à fuse to form long multinucleated fibres (myotubes). • Controlled by many genes (e.g. MyoD, MYF5, myogenin) Cardiac Muscle • From visceral mesoderm surrounding endothelial heart tube. • Myoblasts joined by attachments that become intercalated discs. • Myofibrils develop as in skeletal muscle, but myoblasts do not fuse. Few bundles of muscle cells with irregularly distributed myofibrils become Purkinje’s fibres (conducting system)Embryology • Limb buds first appear end of week 4 on ventrolateral body wall. • Limb morphogenesis takes place between week 4 and week 8 • Lower limb lags slightly behind (1-2 days) but eventually catches up by end of development period.Embryology • First sign of limb buds is condensation of mesenchyme* core surrounded by epithelial ectoderm. Mesenchyme core from parietal layer of lateral plate mesoderm. • *Mesenchyme = mesoderm cells that can develop into connective tissues, blood & vessels. • Epithelial ectoderm thickens at distal border to form Apical Ectodermal Ridge (AER). • AER is key signalling centre controlling adjacent mesenchyme – causes it to remain as undifferentiated, rapidly proliferating cells (progress zone) • As limb grows, cells furthest from AER begin to differentiate into cartilage & muscle. In this manner, development of limb proceed proximodistally.Embryology Steps in Limb Development – proceeds proximodistally forming 3 components: • Stylopod - humerus & femur • Zeugopod - radius/ulna & tibia/fibula • Autopod - carpals, metacarpals, digits, tarsals, metatarsals • At Week 6, terminal portion of limb buds become flattened into handplates and footplates. • Separated from proximal segments by constriction.Embryology • Towards end of week 6, cell death in AER creates separate ridge for each digit. 5 digits grow out under influence of 5 ridge parts. • Mesenchyme condenses to form cartilaginous digits. • By end of week 8, digit separation complete. • Upper limb rotates 90° laterally – extensor muscles lie on lateral & posterior side (thumb laterally, elbows pointing back) • Lower limb rotates 90° medially – extensor muscles lie on anterior surface (big toe lies medially, knees face forward)Embryology Molecular Regulation of Limb Growth • FGF10 from lateral plate mesoderm regulates limb outgrowth • BMPs induce AER • Radical Fringe expression in dorsal half of limb ectoderm restricts location of AER to distal tip of limbs. This gene expression induces SER2. • FGF4 & FGF8 expression in AER regulate progress zone • Limb positioning along craniocaudal axis regulated by HOX genes. • These genes expressed in overlapping patterns from head to tail, with some having more cranial limits than others. • Misexpression of HOX genes alters position of limbs. T-box family transcription factors are involved in controlling forelimb and hindlimb: • TBX-5 expressed in upper limbs • TBX-4 in hind limbs.Embryology Quiz 1. The characteristic event that happens during week 3 of development is called? • Blastocyst • Fertilisation • Gastrulation • Implantation • PlacentationEmbryology Quiz 1. The characteristic event that happens during week 3 of development is called? • Blastocyst • Fertilisation • Gastrulation • Implantation • PlacentationEmbryology Quiz 2. Which of the following are derived from ectoderm? • Adrenal Cortex • Connective Tissue • Gonads • Peripheral nervous system • Thyroid glandEmbryology Quiz 2. Which of the following are derived from ectoderm? • Adrenal Cortex • Connective Tissue • Gonads • Peripheral nervous system • Thyroid glandEmbryology Quiz 3. Which of the following are derived from endoderm? • Dermis of the skin • Epithelial lining of the rectum • Epithelial lining of the lungs • Epithelium of the pituitary gland • Lymphatic systemEmbryology Quiz 3. Which of the following are derived from endoderm? • Dermis of the skin • Epithelial lining of the rectum • Epithelial lining of the lungs • Epithelium of the pituitary gland • Lymphatic systemEmbryology Quiz 4. Which of the following are derived from mesoderm? • Adrenal medulla • Lens of the eye • Muscular system • Parathyroid gland • Skin glandsEmbryology Quiz 4. Which of the following are derived from mesoderm? • Adrenal medulla • Lens of the eye • Muscular system • Parathyroid gland • Skin glandsEmbryology Quiz 5. Which of these muscles is not made from mesoderm? • Cardiac muscle • Intercostal muscle • Muscle tissue in the sweat glandsEmbryology Quiz 5. Which of these muscles is not made from mesoderm? • Cardiac muscle • Intercostal muscle • Muscle tissue in the sweat glandsEmbryology Quiz 6. Which region of the mesoderm will form serous membranes around organs? • Intermediate • Paraxial • VisceralEmbryology Quiz 6. Which region of the mesoderm will form serous membranes around organs? • Intermediate • Paraxial • VisceralEmbryology Quiz 7. Which of the following genes is responsible for skeletal muscle differentiation from the mesoderm? • MyoD • MEF-2 • TGF-βEmbryology Quiz 7. Which of the following genes is responsible for skeletal muscle differentiation from the mesoderm? • MyoD • MEF-2 • TGF-βEmbryology Quiz 8. From which type of mesoderm does cardiac muscle originate from? • Extra-embryonic • Intermediate • Paraxial mesoderm • Parietal layer of the lateral plate mesoderm • Visceral layer of the lateral plate mesodermEmbryology Quiz 8. From which type of mesoderm does cardiac muscle originate from? • Extra-embryonic • Intermediate • Paraxial mesoderm • Parietal layer of the lateral plate mesoderm • Visceral layer of the lateral plate mesoderm