muscle physiology

• muscle is anchored to skeletal insertion points by tendons
• skeletal muscle cells are very large cells and are highly organised

  structure is organised in this way from tissue to sub-cellular level
• sarcomeres are made up of:

  • actin
  • myosin
  • troponin
  • tropomyosin
• myofilaments are made of protein complexes

  thin filaments are made up of actin in complex with troponin and tropomyosin

  thick filaments are made up of myosin that interacts with the thin filament complex via 'myosin heads'

  these two interact to cause contraction through 'cross-bridge cycling'
• cross-bridge cycling

  • cyclic process which is happening all the time and is controlled by action potentials
  • the role of ATP is to cause dissociation between myosin heads and actin
• the smallest unit in controlling movement

  1 alpha motor neuron connected to 1 single axon connected to multiple muscle fibres through synapses called neuromuscular junctions
• synaptic connections occur between:

  • nerve cell-nerve cell
  • nerve cell-muscle cell
  • nerve cell-gland cell
  • sensory cell-nerve cell
• at the synapse, a chemical transmitter released from the presynaptic cell binds to receptors on the postsynaptic membrane
• coupled receptors for AP transfer

  dihydropyridine receptors (DHPR)- voltage-gated channels

  ryanodine receptors (RYR) release calcium from SR into the cytoplasm

  SR<--->t-tubules<--->SR
• Excitation contraction coupling

  1. Signal transduction leads to AP trigger in muscle fibre
  2. AP propagates down sarcolemma and down t-tubules
  3. Depolarisation of t-tubules is sensed by DHPRs → coupled to RYR on the SR
  4. Voltage-dependentCa2+ release
  5. Ca2+is released into the cytoplasm initiating cross-bridge cycling & contraction
  6. Ca2+is pumped back into SR by SERCA terminating crossbridge cycling
• factors which influence the force of contraction:

  1. frequency of APs
  2. number and size of motor units activated
• cardiac muscle is a syncytium

  • striated sarcomere structure is present
  • clusters of cardiomyocytes are termed 'syncytium' and the heart is made up of two of these
  • gap junctions allow for the propagation of action potentials cell to cell
• conduction system of the heart

  1. sinoatrial node is the primary pacemaker region
  2. action potentials spread across atria
  3. atrioventricular node is the secondary pacemaker region. It also delays conduction to the ventricles
  4. conduction propagates slowly through AVN
  5. propagates along the ventricular system consisting of the Purkinje fibres
• cardiac muscle refractory period is 200ms long
• calcium-induced calcium release

  1. action potential breaks down the t-tubules
  2. depolarisation opens through voltage gated Ca2+ channels
  3. Ca2+ influx
  4. Ryanodine receptors open because of rise of Ca2+ concentration
  5. Ca2+ from SR enters cytoplasm through RYR= Ca2+ induced Ca2+
  6. Contraction
  7. Ca2+ rise is transient as Ca2+ pumped into SR (by SERCA) or removed by Na+/Ca2+ exchanger
• Skeletal muscle

  ryanodine receptors- mechanically coupled

  regulation of Ca2+- voltage dependent confirmation change in DHPRs

  contractile force type- all or nothing

  force regulation- action potential frequency leading to sustained tetanus
• Cardiac muscle

  ryanodine receptors- ligand gated

  regulation of Ca2+- calcium induced release

  contractile force type- graded changes controlled by graded Ca2+

  force regulation- Ca2+ grading leads to relaxation, sustained tetanus not normally possible
• Frank-Starling's law of the heart

  • the amount of stretch of the cardiac muscle determines the amount of force generated during contraction
  • the amount of stretch in cellular sarcomeres (i.e. the amount of returning blood, as more blood causes more stretch) determines the amount of force
• positive drug- beta-adrenoceptor agonists: adrenaline, noradrenaline, dobutamine

  • raise cAMP and activate protein kinase A
  • increase calcium channels and calcium release from SR
  • adrenaline is used to treat shock and cardiac arrest
  • dobutamine is sometimes used for acute heart failure
• positive drugs-Cardiac gylcosides; digoxin and ouabain

  • inhibit Na/K ATPase leading to elevated intracellular Na and intracellular calcium
  • digoxin is used to treat heart failure
• negative drugs- calcium blockers: verapamil, diltiazem, nifedipine

  • used to treat cardiac arrhythmias and angina
• negative drugs- beta-adrenoceptor agonists: propranolol, metoprolol

  • used clinically for treating angina, hypertension and cardiac arrhythmias
• physiological functions of smooth muscle:

  • regulating blood pressure
  • peristalsis in the digestive system
  • ciliary and iris muscles in the eye
  • hair standing on end- piloerection
• mechanisms of contraction of smooth muscles:

  • synaptic inputs for the autonomic nervous system
  • circulating hormones, local hormones and metabolites
  • intrinsic activity of paacemaker cells
• regulation of contraction of smooth muscle cells

  Ca2+ release from SR

  • inositol 1,4,5 triphosphate (IP3) receptors
  • ryanodine receptors(RYR)

  Ca2+ influx from

  • voltage-gated calcium channels (DHPR/L-type)
  • ligand gated channels (P2X activated by ATP and ADP
  • store operated Ca2+ channels
• smooth muscle contracts more slowly, but over a larger range of distances than striated muscle
• smooth muscle contractions are not as dependent on action potentials as striated muscle. Contractions may even occur without changes in membrane potential
• intracellular calcium regulates smooth muscle contraction but the sensor is calmodulin (not troponin). These are sarcolemma and SR pathways for Ca2+ entry
• smooth muscle contraction regulated by calmodulin

  • Ca2+ influx from extracellular sources
  • Ca2+ induced Ca2+ release
  • Ca2+---> calmodulin complex
• Ca2+ regulated contraction

  • Ca-Calmodulin phosphorylates MLC-kinase
  • increases ATPase activity
  • causes binding of actin and myosin for contraction
• smooth muscle relaxation

  • elevated local stimuli activate cAMP or cGMP
  • activation of MLCP
  • causes dissociation of actin-myosin interactions
• pharmacological control of smooth muscle contraction

  stimulation of increased intracellular Ca2+

  • agonists of G(ag) coupled receptors to activate SR- Ca2+ release
  • increased opening of voltage-gated channels (ATP on P2X receptors)

  increased sensitivity to Ca2+

  • manipulation of MLC-kinase and MLC-phosphatase activity
• pharmacological control of smooth muscle relaxation

  reducing intracellular Ca2+

  • calcium channel blocker (e.g. dihydropyridines such as nifedipine)
  • drugs and agonists of G(as) coupled receptors that activate potassium channels
  • agonists of Gas coupled receptors. Activation of PKA leads to phosphorylation and inhibition of MLCK
• pharmacological control of smooth muscle relaxation

  reducing intracellular Ca2+

  • calcium channel blocker (e.g. dihydropyridines such as nifedipine)
  • drugs and agonists of G(as) coupled receptors that activate potassium channels
  • agonists of Gas coupled receptors. Activation of PKA leads to phosphorylation and inhibition of MLCK

  inhibiting cross-bridge cycling

  • guanylyl cyclase activators (e.g. nitric oxide, nitrates)
  • cGMP phosphodiesterase inhibitors (e.g. sildenafil/viagra)
• noradrenaline leads to:

  • constriction of many blood vessels
  • dilation of bronchi in lung airways
• latch state physiology

  • maintenance of prolonged contraction without ATP utilisation
  • Ca2+ falls and MLCK activity is reduced
  • cross bridges stay bound to actin for longer and generate force
• differences between 3 types of muscle