Topic 1:Intro to Muscles Motility & Force Generation

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Topic 1:Intro to Muscles Motility & Force Generation
2014-01-09 03:31:00
Systems 1
Lecture 1.1
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  1. Types of Muscles
    • 1. Striated (skeletal + cardiac)
    • 2. Smooth
  2. Striated Muscles
    highly organized into sarcomere structures giving a “striated” appearance under the microscope
  3. Skeletal Muscles
    performs mechanical work via the skeleton under voluntary neural control
  4. cardiac muscles
    performs mech work in the heart under its own pacing control modulated by ANS
  5. Smooth Muscle
    contractile apparatus is loosely organized without a defined banding pattern
  6. Smooth Muscle
    performs mechanical work in many target organ systems and is modulated by NT's, metabolic, local and hormonal factors.
  7. Features of skeletal muscles
    1. Cells are multinucleated, striated and organized in parallel bundles

    • 2. Diameters-->10 mm - 100 mm
    •    lengths --> 1 mm - 20 cm

    • 3. Activated by motor neurons from CNS
    • (spinal cord) at neuromuscular junctions leading to muscle action potentials and
    • voluntary contraction
  8. Features of Smooth Muscles
    1. no attachments to a skeleton which limit movement

    • 2.cells are much smaller and attached (physically & electrically) to each
    • other via Gap Junctions.

    3.spindle shaped mono-nucleated cells w/ short lengths of  50 – 400 μm and diameters of 2 – 10 µm

    4.found in a wide variety of organ systems
  9. features of cardiac muscles
    1. cells aka "myocytes" 

    2. diameter: 25 mm; length: 150 mm

    3. 2 nuclei

    4. myocytes are striated.

    5. organized in layers/"syncytium"

    6. connected by intercalated discs with gap junctions.

    7. Myocytes are not individually innervated, but regions innervated by neurons from ANS.

    8.Mechanical activity is rhythmical paced SA node of the right atrium (modulated by NT)
  10. Structure of skeletal muscle from largest to smallest
    muscle > myofiber > myofibril
  11. Structure of cardiac muscles
    • - has a "field" structure
    • - formed from a syncytium of cells, not from distinct fibers.
  12. components of ECM & Cytoskeleton
    • 1. Collagen Matrix
    • 2. Dystroglycan Complex (Dystrophin)
  13. Collagen Matrix
    • - surrounds entire muscle fibers
    • - collagen laid down by fibroblasts
  14. Dystroglycan Complex (Dystrophin)
    - protein complex that helps w/ membrane stability of muscles

    - lack of dystrophin leads to Muscular Dystrophy
  15. Sarcomeres
    - what is it?
    - present in what type of muscles
    - basic repeating contractile units in striated muscle

    - present in skeletal and cardiac
  16. A band
    I band
    H zone
    - A band = dark = thick filament = whole length of myosin superimposed by actin

    - I band = light = thin filament = actin only

    - H zone = region of myosin only
  17. 2 other components of sarcomeres
    1. Alpha-actinin: interacts w/ thin filaments @ Z line

    2. Titin filament: runs for M line to Z line and tethers both the thin and thick filament together (keeps sarcomere in line)
  18. organization of skeletal vs cardiac muscle
    Skeletal: organized into large fibers to form whole muscles

    Cardiac: organized into “syncytial field” structure of individual myocytes
  19. which bands/zone changes during sarcomere contraction?
    I band and H zone SHORTENS

    A band remains the SAME
  20. The Sliding Filament hypothesis
    the basis of striated muscle force generation and shortening
  21. What components is the molecular motor that generates force and movement in muscle?
  22. Components of Myosin molecule
    - Each thick filament contains hundreds of myosin molecules which contain:

    • 1. S1 region
    • 2. S2 region
    • 3. Light Chains (ELC + RLC)
  23. S1
    • - business end of the mysosin molecule
    • - regions that binds to the actin
    • - contains ATP pocket (myosin is an ATPase)

  24. S2
    • - "rope" part of the myosin
    • - has a swivel that allows it to stick out
    • - springy elastic protein
  25. Light Chains
    • (1) ELC 
    • (2) RLC = regulatory light chain
  26. Force is Generated by?
    • - Hydrolysis of ATP
  27. Why are there 2 S1 heads on myosin?
    - double head arrangement increases the probability of actomyosin binding and cycling via cooperativity

    - angles at which the crossbridges stick out of the thick filament do not  line up w/ each thin filament

    • - double heads improve likelihood of alignment and increase contractile
    • efficiency.

    • •Both
    • heads are otherwise independent force generators.
  28. Crossbridge Cycle
    • Start: "energized crossbridge" = ADP + Pi bound to myosin head
    • 1. Crossbridge binds to actin
    •      - due to rise in [Ca++]
    • 2. Crossbridge moves/bound more tightly
    •     - due to release of ADP + Pi
    • 3. Crossbridge detaches
    •     - due to ATP binding to myosin
    • 4. Energize Crossbridge
    •     - due to hydrolysis of ATP to ADP
  29. Do the crossbridges actually generate force and move the filaments?
  30. Which protein component generates the force in this actomyosin complex?
    S1 Head conformational change.
  31. Where is the actual conformational change to generate movement?
    Between the head region and the light chains of myosin
  32. How much force does it generate and how far might it move/ATP?
    For Myosin II (striated &smooth muscle) molecular motor can generate up to 10 pN with a stroke in the 5-10 nm/CB cycle range
  33. Other Motor proteins
    There are 17 Families & ~140 Distinct Motor Proteins

    Myosin II is only a small portion of motor proteins
  34. what regulates muscle contraction?
    what is it released by?
    Ca++. Released by sarcoplasmic reticulum under the control of electrical stimulation via action potentials
  35. Ca++ interact with what to regulate muscle contraction?
    troponin and tropomyosin.
  36. how to troponin and tropomyosin help with regulation?
    regulate the crossbridge cycle by covering and uncovering myosin binding site on actin depending upon [Ca++]

    Tropomyosin = rope-like (covers up myosin crossbridge binding site on actin)

    Troponin = physically binds with Ca++
  37. Molecular characteristics of Troponin
    - consists of 3 sub-units.

    1. Troponin T (TnT) binds tropomyosin @ every 7 actin molecules

    2. Troponin I (TnI) physically inhibits binding of myosin to actin when no Ca++ is present.

    3. Troponin C (TnC) binds Ca++.
  38. When Ca2+ is bound, what happens to TnI?
    the conformation changes moving TnI off the myosin binding site on actin permitting crossbridge cycling
  39. Features of TnC?
    Diff btwn TnC in skeletal and cardiac?
    There are 4 Ca2+ binding sites on TnC: 2 are always filled by Mg2+ and the other 2 can bind Ca2+

    • cardiac: One of the two Ca2+ binding sites
    • on cardiac troponin is not functional

    therefore, it only takes 1 Ca++ ion to activate whole system for cardiac. Skeletal requires binding of 2 Ca++
  40. How does cardiac muscle initiate the
    contraction/ relaxation cycle necessary for the heart to beat?
    Excitation Contraction Coupling
  41. Excitation Contraction Coupling
    • EC coupling is the sequence of events that link the depolarization of the surface membrane with tension development by the
    • contractile machinery
  42. EC coupling in cardiac muscles are initiated by?
    the propagation of an action potential along the sarcolemma
  43. Are Cardiac Myocytes individually innervated?
    No! They also have no direct CNS input
  44. Rate and magnitude of cardiac contractions are modulated by?
  45. How is Ca++ released in cardiac muscles?
    Calcium is released from SR like in skeletal muscle, but it also directly enters the cell from the outside via calcium channels.
  46. how is cardiac muscle AP diff from other muscles?
    compared to nerve or skeletal muscle, cardiac muscle has a much longer action potential duration due to the Ca2+ conductance.
  47. Cardiac EC Coupling Sequence [Contraction]
    • 1. depol of plasma membrane
    • 2. opening of voltage-gated Ca++ channels in T-tubules
    • 3. influx of Ca++ in cytosol
    • 4. Ca++ binds to Ca++ receptors on SR
    • 5. more influx of Ca++ in cytosol
    • 6. increase cytosolic [Ca++] --> contraction
  48. How much of Ca++ comes from SR vs outside?
    • In humans and large mammals,
    • 70% of the Ca++ comes from the SR
    • 30% from the outside
  49. Cardiac EC Coupling Sequence  [Relaxation]
    Ca++ must be proportionally pumped back to both reservoir sources for relaxation to occur
  50. Ways to re-sequester Ca++ in cardiac muscle relaxation
    • 1. SR Ca2+ pump
    • - resequesteres intracellular Ca2+ from
    • the SR
    • - rate of resequestration is modulated by phospholamban (PLB)
    • - process uses ATP

    • 2. Sodium-Calcium Exchanger
    • - extrudes extracellular portion of Ca2+
    • - 3Na/1Ca, no ATP used

    • 3. T-Tubule Ca-pump
    • - extrudes extracellular portion of Ca2+
  51. Ryanodine receptors
    - mediate the release of calcium ions from the sarcoplasmic reticulum

    - releases calcium upon calcium binding
  52. what type of regulation does cardiac and skeletal muscle have?

    (hint: think of sigmoidal graph)
    Allosteric Regulation (cooperative)
  53. Cardiac & skeletal muscle
    have slightly different forms of EC coupling 
    primarily differentiated by?
    the sources of calcium necessary to initiatecontraction.