Skeletal Muscle

Question 1

General Skeletal Muscle Anatomy

Answer 1

• Skeletal muscle functions:
  
  • Ambulation
  • Blood glucose storage
  • Post-prandial lipid oxidation
  • Thermogenesis (2^nd to live)
• Distinct regions of muscle tissues are electrically excitable (electrogenic)
• AP at muscle cell plasma membranes
• Contraction
  
  • Isometric (no movement)
  • Isotonic (force and movement)
• Muscle fibers are surrounded by sarcolemma (specialized plasma membrane with tough outer coat of collagen/polysaccharide
• Muscle fiber > myofibrils
  
  • Myofibril
    
    • Repeating sarcomeres > myofilaments > actin/myosin
    • Sarcoplasm
      
      • Sarcoplasmic reticulum (stores Ca2+)
        
        • SR membrane has many voltage gated Ca2+ channels and ATPases > Ca2+ flux between SR / sarcoplasm
      • Calsequesterin (binds and maintains Ca2+)

Question 2

Sarcomere Organization

Answer 2

• Sarcomere organization
  
  • A band (myosin and actin)
  • I band (only actin)
  • H band (only myosin)
• Myosin
  
  • 2 heavy chains
    
    • Tails and anchoring
  • 4 light chains
    
    • Myosin head region
    • ATPase
• Actin
  
  • Filamentous
  • Made of:
    
    • G actin
    • Troponin (blocks myosin binding site)
      
      • I, T, C
    • Tropomysin (myosin binding domains within actin)

Question 3

Muscle Contaction: Excitation-Contraction Coupling

Answer 3

• At neuromuscular junction / motor end plate / myoneuronal junction
• Pathway:
  
  • AP down unmyelinated efferent motor neuron
  • Nerve terminus (lots of mitochondria and NT vesicles ACh)
  • Voltage gated Ca2+ channels open
  • Ca2+ influx
  • Vesicles fuse with presynaptic membrane
  • Ach released to junctional cleft
  • Ach binds cholinergic-nicotinic receptors at the post-junctional membrane of sarcolemma
• Deactivated of signal
  
  • Ach degraded by acetylcholinesterase
  • Diffusion out of synaptic cleft
  • Myasthenia gravis
    
    • Acetylcholinesterase inhibited > Ach in cleft for longer > longer muscle contraction
• Cholinergic-nicotinic receptors = ligand-gated ion channels
  
  • Na influx
    
    • End plate potentials (EPP) subthreshold depolarizations
  • K efflux

Question 4

Calcium Release From SR to Sarcoplasm

Answer 4

• AP > t-tubules > DHPR change conformation > Ryr open > Ca2+ from SR to sarcoplasm junctions = z-disk > contraction
  
  • T-tubules
    
    • Transverse tubules
    • Highly conductive specialized structures that propagate AP to deep region of muscle cells
  • Dihydropyridine receptors (DHPR)
    
    • In t-tubule
    • Site on Ryanodine receptor (Ryr) channels
      
      • DHPR conformational change > opens Ryr > Ca2+ flow from SR (high [Ca]) to sarcoplasm
    • Voltage gated Ca2+ channgels
  • Sense AP > conformational change
• Z-disk
  
  • Triad junctions localized here

Question 5

Troponin/Tropomyosin Complex

Answer 5

• Contraction
  
  • Ca2+ binds troponin C > conformational change of troponin/tropomysin complex > myosin binding site on actin exposed > actin and myosin couple < myosin conformation change = powerstroke (pulls actin) > Z band shortens
• At rest, high energy myosin-ADP+P complex maintained
  
  • High affinity for ATP
  • Binds actin when site exposed
• Muscle contraction begins with isometric contraction (tension but not movement) > isotonic contraction (movement)
• Contraction cycle continues as long as ATP available and Ca2+ high

Question 6

ATP and Muscle Contraction

Answer 6

• 1^st source of ATP: Basal ATP stored
• 2^nd source of ATP: Phosphocreatine (pCr)
  
  • Generates ATP
  • Creatine kinase catalyzes pCr + ADP > Cr + ATP
  • pCr regenerated at rest
• Additional sources of ATP for prolonged contraction:
  
  • Glycolysis – not efficient (seconds to 1 minute)
    
    • 1 glucose > 2 ATP + lactate
  • Oxidative metabolism** (hours?)
    
    • 1 glucose + 6O2 > 6 CO2 + 6H2O + 38 ATP
  • Fatty acids (hours of muscle activity)
    
    • Adipocytes: triglycerides + epinephrine and growth hormone > free-fatty acids
    • 1 fatty acid + oxygen > water + 129 ATP

Question 7

Ca2+ and ATP

Answer 7

Question 8

Muscle Relaxation

Answer 8

• Sarcoplasmic Endoplasmic Reticulum Ca2+ ATPase (SERCA)
  
  • Protein on SR membrane > pumps Ca2+ from sarcoplasm to SR
  • Active transport
  • Low/no Ca2+ in sarcoplasm > muscle relaxation
• Leak channels
• Na+-Ca2+ exchanger (NCX) channels
  
  • Lower sarcoplasmic Ca2+
  • Skeletal muscle and cardiomyocytes
  • Block NCX > elevated sarcoplasmic Ca2+ > positive inotropy!

Question 9

Muscle Twitch

Answer 9

• Single rapid muscle contraction in response to a single AP
• Summation
  
  • Multiple fiber summation
  • Will recruit as many motor units as necessary to displace the load
  • Simultaneous contraction of many motor units
• Temporal//Frequency Summation
  
  • Increased frequency of contraction per time
• Tetany
  
  • Rapid successive twitches fuse
  • Maximum strength of contraction
  • Not aware of muscle twitch? Occurs before contraction (is a spasm)

Question 10

Muscle Growth, Exercise, Catabolism

Answer 10

• Type 1 and 2 scattered through skeletal muscle
• Fiber types:
  
  • Type 1
    
    • Slow twitch
    • Red
    • Oxidative
    • Sustain activity over long periods of time
    • Low intensity endurance training > increase oxidative capacity of Type 1 (increase mitochondria and capillary density)
    • Small diameter > well vascularized (red) > oxidative metabolism for energy
    • Sustained aerobic muscle activity
      
      • Marathon runners
  • Type 2
    
    • Fast twitch
    • White
    • Glycolytic
    • Rapid generation of force over short periods of time
    • Endurance training > increase oxidative capacity
    • High resistance training > Type 2 hypertrophy
    • Large diameter > greater force of contraction
    • Extensive SR, lower mitochondria
    • Types
      
      • Type 2a
        
        • Low oxidative capacity
      • Type 2b
        
        • No oxidative capacity
        • Anaerobic, rapid power movements
        • Weight lifter / football lineman
• Hypertrophy
  
  • Increase diameter of muscle fibers > increase muscle strength
  • Regular demand > proliferation of vasculature > gain of muscle mass
    
    • Angiogenesis (vasculature synthesis) stimulated by growth factors
• Exercise induces upregulation in:
  
  • Mitochonidral number and function
  • ATP and phosphocreatine content
  • Intramusculuar glycogen stores
  • Intramuscular triglyceride levels
• Sarcopenia
  
  • Age related loss of muscle mass
  • Beings in 30s

Question 11

Brief Introduction to Blood Pressure Regulation

Answer 11

• BP = CO X TPR
  
  • Blood pressure
  • Cardiac output
    
    • Increase CO = Increase BP
      
      • Positive inotropes
        
        • Epinephirine
        • Digoxin
  • Total peripheral resistance
• Vascular smooth muscle
  
  • Mostly in arteries (than veins)
  • Controlled by
    
    • Sympathetic NS (vasoconstriction)
    • Hormones
    • Metabolites
      
      • Nitric oxide, CO2, lactate, adenosine
  • Factors that activated membrane Ca2+ channels > contraction > vasoconstriction > elevated BP