Muscle physiology Flashcards
Motor unit
Alpha motor neuron + all the muscle fibres it innervates
Type I muscle fibres are:
Slow
Type II muscle fibres are:
Fast
Size principle
Small oxidative units recruited first because of their lower threshold, large glycolytic motor units last
Neuromuscular junction
Motor axon synapses on the motor end plate of the motor neuron. The axon loses its myelin sheath and splits into multiple branches.
2 distinct domains of the postsynaptic folds
Crests and depths of the folds
The crests of the postsynaptic folds have:
High concentration of AChRs, rapsyn and utrophin
Rapsyn
AChR clustering proteins
Utrophin
Ubiquitous dystrophin
The depths of the postsynaptic folds have:
High concentration of voltage gated sodium channels
Presynaptic events at the neuromuscular junction
1) AP reaches nerve terminal
2) Depolarisation opens VGCCs
3) Ca+2 influx
4) Increased Ca+2 triggers vesicle exocytosis and ACh release
Vesicle cycling and release
1) Vesicles filled
2) Vesicles form vesicle cluster
3) Filled vesicles dock at active zone
4) Vesciles are primed
5) Ca+2 triggered fusion-pore opening
6) Vesicles undergo exocytosis
7) Recycling of vesicles
3 ways vesicles can be recycled
Local reuse
Fast recycling
Clathrin mediated endocytosis
Postsynaptic events at the neuromuscular junction
1) ACh binds transmitter gated channels
2) Channels open
3) Na+ inflow, K+ outflow
4) Depolarisation of motor endplate
5) VGNCs open
6) Na+ inflow
7) Depolarisation
8) Propagated muscle AP
AChE
Acetylcholinesterase
Anchored to collagen fibrils of basement membrane
AChE works by:
Rapidly hydrolysing ACh with water to form choline and acetate
Choline diffuses back to presynaptic terminal and is reabsorbed
3 presynaptic examples of abnormal neuromuscular transmission
Lambert-Eaton syndrom
Diabetes
Botulinum and tetanus toxins
2 postsynaptic examples of abnormal neuromuscular transmission
Myasthenia Gravis
Alpha toxins
Myasthenia Gravis key points
Autoimmune - antibodies attack AChRs
Reduces number of functional receptors and inhibits AP initiation
Treated with anti-AChEs and immunosuppressants
Botulism key points
Botulinum toxin released by Clostridium botulinum
Toxins bind presynaptic terminal, are internalised and catalyse cleavage and inactivation of vesicle release system
Blocks depolarisation induced quantal release
Recovery only occurs when nerve terminals grow new sprouts to escape toxins and form new contacts with the muscle fibre
4 characteristics of skeletal muscle
Excitable
Contractile
Extensible
Elastic
Epimysium
Surrounds entire muscle
Perimysium
Surrounds entire fascicle
Endomysium
Surrounds each muscle fibre
Sarcolemma
Cell membrane of the muscle fibre
Na+ concentrations inside and outside cell
Inside: 10 mM
Outside: 145 mM
K+ concentrations inside and outside cell
Inside: 145 mM
Outside: 4 mM
Ca+2 concentrations inside and outside cell
Inside: 0.1 microM
Outside: 1.5 mM
Transverse tubular membrane system
Deep invaginations of sarcolemma into myocyte
Conduct propagated APs and result in localised contracture of filaments
T-tubule location
Either side of myosin strip at junction of overlap between A and I bands
Triad
T-tubule + 2 terminal cisternae of the sarcoplasmic reticulum
Essential for synchronised excitation-contraction coupling
Sarcoplasmic reticulum function
Stores Ca+2
3 major classes of SR calcium-regulatory proteins
Luminal calcium binding proteins
SR calcium release channels
Sarcoplasmic reticulum Ca+2 ATPase pumps (SERCA)
Basic unit of contraction
Sarcomere
A band
Both thick and thin filaments
Anisotropic
I band
Only thin filaments
Z line
Electron dense region in the middle of the I band
H band
Only thick filaments
M line
Electron dense region in the middle of the H band
Actin filaments attach:
At the Z line
Myosin filaments attach:
At the M line
Thick filament composition
Myosin pairs oriented in opposite directions, staggered around fibre
Thin filament compostion
Two strands of F-actin twisted together with tropomyosin molecule lying along the helix in a groove
Titin
Acts as a spring connecting myosin to Z line
Heads of myosin are present along the sarcomere except in:
The H zone
Nebulin
Helps align thin filaments
3 parts of troponin complex
TnT
TnC
TnI
TnT
Troponin tropomyosin
Positions complex on tropomyosin molecule
TnC
Troponin calcium
Contains Ca+2 binding sites
TnI
Troponin inhibitor
Binds actin and inhibits myosin head from binding to the actin binding site in the process
Troponin complex + tropomyosin =
Ca+2 sensitive switch
Roles of ATP in cross-bridge cycle
ATP + myosin binding breaks link formed between actin and myosin
ATP hydrolysis provides energy for cross-bridge movement
6 steps of cross-bridge cycle
1) Myosin bound to actin
2) Myosin dissociation
3) ATP hydrolysis
4) Conformational change
5) Power stroke
6) Myosin binds actin
Describe Step 1 - Rigor state of the cross-bridge cycle
Myosin is tightly bound to actin at the actin binding site. The myosin head is at 45° relative to the filaments
Describe Step 2 - Myosin dissociation of the cross-bridge cycle
ATP binds nucleotide binding site on the myosin which changes the configuration of the myosin head and allows it to dissociate from the actin binding site
Describe Step 3 - ATP hydrolysis of the cross-bridge cycle
ATPase activity of myosin hydrolyses ATP into ADP + P. At this stage, both products are still bound to myosin which is unbound from actin.
Describe Step 4 - Relaxed state of the cross-bridge cycle
Myosin head swings over and binds weakly to a new actin molecule, changing the angle from 45° to 90° relative to the filament. ADP and P are still bound to myosin.
Describe Step 5 - Power stroke of the cross-bridge cycle
P dissociates from the myosin head which causes the head to rotate on its hinge back to 45°. It is still attached to the same position on the thin filament and therefore pushes the thin filament back with it - therefore power stroke.
Describe Step 6 - Repositioning of the cross-bridge cycle
After power stroke the ADP dissociates from the myosin head. With this conformational change the myosin forms the rigor state attached to the actin once again.
At rest, tropomyosin prevents:
Interaction between actin and myosin
Troponin C has ____ Ca+2 binding sites
4
2 high affinity and 2 low affinity
The binding of the 2 extra Ca+2 to troponin C causes:
The conformational change in the troponin complex which allows tropomyosin to shift in respect to the actin filament
The mechanical coupling hypothesis
High density of dihydropyridine receptors in tetrads opposite 4 ryanodine receptors in SR terminal cisternae. Depolarisation of TT membrane flips DHPR, inducing conformational change in RyR which allows them to become open Ca+2 channels. Therefore DHPRs are essential for excitation-contraction coupling.
4 benefits of voltage dependent excitation contraction coupling
1) Rapid kinetics
2) No dependence on current flow
3) No reliance of diffusion of substances from sarcolemma
4) Activation can occur in absence of extracellular Ca+2
Isometric contraction
No external shortening takes place
Same length
Force of weight = force developed by muscle
Isotonic contraction
Movement takes place
Same force
2 types of isotonic contraction
Concentric
Eccentric
Concentric contraction
Force of weight is less than force developed by muscle
Muscle shortens
Eccentric contraction
Force of weight is more than force developed by muscle
Muscle lengthens
Force velocity relationship
Load opposing contraction increases so velocity of shortening decreases
Force = ?
Mass x Acceleration
Work = ?
Force x Distance
Power = ?
Work / Time
Type 1 slow twitch fibres
Red due to myoglobin
Lots of mitochondria
Resistant to fatigue
Abundant in postural muscles and endurance athletes
Type 2a fibres
Fast oxidative Hybrid of type I and II fibres Red, lots of mitochondria Anaerobic and aerobic More prone to fatigue than type I
Type 2b fibres
Fast glycolytic White Anaerobic Fatigue rapidly Lots of power
3 causes of muscle weakness
Muscle fatigue
Muscular dystrophy
Sarcopenia
Muscle fatigue
Failure to maintain required or expected power output
Reduced muscle performance
Central fatigue
Muscle fatigue resulting from decreased activation from CNS and decreased number of motor units recruited
Peripheral fatigue
Muscle fatigue resulting from affected cellular mechanisms that control force such as smaller Ca+2 transient, reduced Ca+2 sensitivity of myofilamentsand slower crossbridge cycling
Proposed causes of fatigue
Accumulation of metabolites
Depletion of muscle energy supplies
4 key metabolite products that could accumulate
Lactic acid
Extracellular K+
Inorganic phosphate
ROS
4 key products that could be depleted
Glucose
Creatine phosphate
ATP
Oxygen
Duchennes muscular dystrophy
Mutation in dystrophin gene causes loss of dystrophin
Increased membrane permeability leads to skeletal muscle weakness and degeneration
Respiratory failure common around age 20
Sarcopenia
Age related loss of muscle function
Muscle mass/body mass ratio decreases leading to significant loss of strength
