Muscle and Cardiovascular system

• The three types of muscle:

  • Skeletal: large fibres, multinucleated cells and striated. High mitochondria concentration
  • Cardiac: small fibres, branched but striated and contain intercalated discs (junctions)
  • Smooth: not striated
• Skeletal muscle is attached to bone by tendons which are comprised of:

  • type I and III collagen
  • Elastin
  • Proteoglycans
  • Tendon fibroblasts
• Striations are due to the alternating dark, thick myosin and light, thin actin molecules in sarcomeres
• Skeletal muscle organisation:

  • Epimysium: wraps around muscle to connect to tendon
  • Fascicle: collection of muscle fibres
  • Perimysium: separates fascicles
  • Endomysium: separates muscle fibres within fascicles
  • Sarcolemma: muscle fibre cell membrane
  • Myofibril: sarcomere protein units (actin and myosin)
• Sarcomeres consist of actin and myosin filaments:

  • Z line: where actin ends connect
  • M line: middle of sarcomere and contains myosin
  • A band: contains the whole length of myosin filament
  • H zone: the area of myosin that does not contain actin
  • I band: the area of actin that does not contain myosin
• During a muscle contraction, the A band remains the same length whilst the H zone and I band decrease in length
• Titin gives rise to the muscle's elastic, passive force
• A muscle triad contains the T tubule with sarcoplasmic reticulum on either side of it
• Cardiac muscle (myocardium) contains 99% contractile cells (sarcomere) and 1% autorhythmic pacemaker cells which start myocardium contraction and set heart rate
• Cardiac muscle contraction:

  • Calcium ions enters cell due to electric waves of depolarisations generated from intercalated disc opening voltage gated calcium channel
  • Calcium that has entered binds to RyR, allowing sarcoplasmic calcium to enter cytoplasm
  • Cytoplasmic calcium binds to troponin to signal contraction
• Cardiac muscle relaxation includes actively transporting calcium and using Na+/K+ATPase pumps to regulated extracellular voltage
• Smooth muscle contains more actin and longer myosin chains. Myosin heads are in opposite directions and so produce opposite forces either side
• Smooth muscle contraction:

  • Calcium enters cell or is released from sarcoplasmic reticulum
  • Cytoplasmic calcium binds to calmodulin, activating MLCK
  • Active MLCK phosphorylates myosin heads, allowing for crossbridges to form
• Smooth cells are either:

  • Single-unit smooth muscle: coordinated smooth muscle contraction where varicosities excite one layer of muscle and rest is activated by gap junctions
  • Multi-unit smooth muscle: no gap junctions so varicosities excite all muscle cells. Allows for more fine focus contractions
• Phasic smooth muscle: usually relaxed

  Tonic smooth muscle: usually contracted
• Myosin heads have two important sites:

  • actin binding site
  • myosin ATPase site
• Thin filaments contain four proteins:

  • Actin
  • Tropomyosin: blocks myosin head from binding to G-actin molecules
  • Troponin: allows for tropomyosin to rotate away from G-actin molecules once calcium ions binds to it
  • Nebulin: binding protein in middle of thin filament
• Sarcomere muscle contraction:

  • Calcium binds to troponin
  • Tropomyosin rotates, allowing actin binding site of myosin head to bind to G-actin molecules on thin filament
  • ATP is hydrolysed by ATPase, allowing for the myosin ATPase site to become phosphorylated
  • Hinge point undergoes conformational change to move thin filament to decrease size of H zone (power stroke)
  • ADP unbinds, detaching actin binding site of head off from thin filament
  • Actin binding site finds a new distal G-actin molecule to bind to, causing a crossbridge cycle to occur
• Excitation-contraction coupling:

  • Depolarisation on motor neuron opens voltage gated calcium channels, causing exocytosis of acetylcholine vesicles using docking proteins
  • Acetylcholine binds to non-specific cation channel nicotinic receptors in neuromuscular junction, causing influx of sodium ions and thus a depolarisation event
  • Depolarisation continues into T tubule and activates DHP to open RyR calcium channel in sarcoplasmic reticulum
  • Cytoplasmic calcium concentration increases, leading to sarcomere crossbridge cycling
• The twitch is a mechanical response to a single action potential. After the action potential, there is a latent period, followed by an increase in tension during the contraction time to a maximum contractile response which then leads to muscle relaxation time
• An action potential always releases the same number of calcium ions from the sarcoplasmic reticulum, leading to the same number of binding sites available for cross bridge cycling and so same force generated
• One motor neuron innervates at a number of muscle fibres but each muscle fibre only has one motor neuron innervating in it. One action potential from a motor neuron excites all muscle fibres innervated in it (motor unit)
• Every muscle has an optimal length at which maximum active force (due to cross bridge cycling) can be achieved
• Energy states of myosin head:

  • ATP binds to myosin head, causing head to detach from G-actin molecules on thin filament
  • ATP is hydrolysed, requiring energy, so causes the energy state to increase
  • ADP and Pi are on myosin head causing cocking
  • Head hinges onto G-actin molecule (after calcium binds to troponin)
  • Pi is released from head, leading to a power stroke (rigor)
  • After power stroke, ADP is released
• Three sources of ATP production:

  • Creatine phosphate (with creatine kinase): short term
  • Anaerobic gylcolysis (glucose): medium term since it requires GLUT-4 transporters on myocytes
  • Oxidative phosphorylation: long term. During exercise, a decrease in available oxygen causes oxidative phosphorylation to decrease in activity
• Types of muscle contraction:

  • Isotonic (constant tension): muscle fibre changes in length:
  • Concentric: muscle shortens in length and the force generated is greater than the load
  • Eccentric: muscle lengthens and the force generated is less than the load
  • Isometric: muscle fibre length remains constant but force generated is less than the load
• Types of skeletal muscle fibres:

  • Slow twitch: oxidative, requires O2 which is binded to dark coloured myoglobin, fatigue resistant
  • Fast twitch: glycolytic, larger diameter, pale colour, easily fatigued
• Factors affecting force:

  • Cross sectional area of muscle
  • Number of sarcomeres in parallel (in series impacts velocity)
  • Number of active motor units
  • Intracellular calcium, oxygen and ATP
  • Initial muscle length
  • Fatigue
• Sources of fatigue:

  • Extracellular potassium
  • Muscle acidosis
  • Pi accumulation
  • Depletion of glycogen
• Active motor unit summation increases maximum muscle tension where frequency of stimulus and calcium release is greater than calcium cleared. This will generate a force larger than a single twitch

  Tetanus is when a peak force is generated through summation
• As muscle length increases, active force decreases but passive force increases due to parallel elastic components (cell membrane and titin) and series elastic components (tendons)
• Blood is composed of cellular elements including red blood cells (erythrocytes) for oxygen and carbon dioxide transport, white blood cells (leukocytes) for immunity and platelets (thrombocytes) for coagulation
• Haematopoiesis (blood cell production) begins early in embryonic development and continues throughout life. It occurs in bone marrow (red is active and yellow is inactive), producing 75% WBC and 25% RBC, where this production is controlled by cytokines
• Erythropoiesis is controlled by glycoprotein erythropoietin (EPO) and some cytokines. Hypoxia (low oxygen concentration) triggers EPO release from kidneys which travels to red bone marrow, increasing oxygen carrying capacity
• Blood diagnostics involves complete blood count (CBC) provides information about the blood components. Haematocrit determines the percentage of RBC volume of the total blood volume. Four classifications are below:

  • Normal: 45% haematocrit
  • Anemia: 30% haematocrit
  • Polycythemia: 70% haematocrit
  • Dehydration: 70% haematocrit due to a decrease in plasma %(v/v)
• Erythrocytes do not contain organelles nor a nucleus. Instead, they have a biconcave disc structure to increase surface area for oxygen transport. They also have a flexible membrane to prevent rupturing across narrow capillaries
• Erythrocyres contain haemoglobin which is responsible for transporting oxygen. Haemoglobin is comprised of four globular protein chains, two are alpha chains and two are beta chains. Each chain is wrapped around a heme group, containing a central iron atom which binds to oxygen. Hence, one haemoglobin can bind up to four oxygen atoms
• Iron is mostly consumed from diet and absorbed through small intestines. Once in the plasma of blood (also from excess iron stores in liver), it is transported to red bone marrow by binding to transferrin. Then, iron forms into heme, haemoglobin and then red blood cells (erythropoiesis). These red blood cells last 120 days in the blood before the spleen destroys them, converting haemoglobin into bilirubin (yellow in colour). Bilirubin is then either excreted by kidneys in urine or is metabolised and excreted in bile.
• Sickle cell disease is the polymerisation of haemoglobin when it gives up oxygen and is a genetic defect changing the 6th amino acid in beta chain from glutamate to valine
• An anti-X antibody can bind to an X antigen, causing agglutination (clumping of antigen targets)