Week 3.3 Muscle Function

Alpha Motor Neuron

-One neuron that synapses with multiple muscle fibers

-Provides excitation for muscle fibers to generate tension

Motor Unit

-The alpha motor neuron and the skeletal muscle fibres it innervates

-Follow an "all or none" principle

What does "all or none" principle mean?

-When a motor unit is stimulated, all muscle fibers in that motor unit will fire

Motor Pools

-Motor neurons are grouped together on the longitudinal axis of the spinal cord

-Across one or more spinal cord segments

-All the motor neurons that innervate a single muscle

Neuromuscular Junction (3 parts)

-Connection between motor neuron and a muscle fiber

-Each muscle fiber has its own

3 parts:

1. Presynaptic Terminal

2. Synaptic Cleft

3. Postsynaptic Muscle Fibre (motor endplate)

Presynaptic Terminal

-End of the motor neuron

Synaptic Cleft

-Space between presynaptic neuron and postsynaptic muscle fibre

-Where presynaptic NT (ACh) is released

Postsynaptic Muscle Fibre (motor endplate)

-Contains ACh receptors

NMJ: steps

1. Depolarization of the presynaptic membrane causes influx of Calcium

2. Acetylcholine is released into synaptic cleft via vesicles

3. Acetylcholine binds to the receptors on motor endplate

4. Causes depolarization of motor endplate (end plate potential)

5. End plate potential triggers an AP if reaches threshold

What happens after the synaptic transmission at the NMJ?

-Acetylcholine is broken down by the enzyme acetylcholinesterase and the vesicles are recycled

Acetylcholinesterase

-Acetylcholine is broken down by this enzyme after synaptic transmission

Safety Factor at NMJ

-Motor neurons release excess ACh to depolarize postsynaptic membrane (bc there are enough receptors so signal is so strong that it goes well above the threshold)

-This ensures neuromuscular transmission to remain effective under different conditions

-Increases chance that muscle will contract, even when fatigued

Define Safety Factor

-Margin by which the end motor plate exceeds the threshold needed to trigger a muscle AP

"how much extra-depolarization" there is beyond what is required for an AP

Myasthenia Gravis (Safety Factor)

-Results in a loss of acetylcholine receptors in the muscle fiber = reduced membrane depolarization

=Smaller safety factor (less depolarization above the threshold)

-With repeated firing, some vesicles may release slightly less ACh each time, so some fibers don't fire = overall drop in muscle force = fatigiable weakness

Muscle Structure

-Made up of fasicles which are made up of muscle fibres which are made up of myofibrils

Sarcolemma

-Each muscle fibre is surrounded by this (cell membrane)

-Allows depolarizing current to reach the sarcomeres through T-Tubules

Myofibril

-Smallest part of the muscle

-Contains the sarcomere

Sarcoplasmic Reticulum

-Stores, releases and retrieves calcium

-Embedded between myofibrils

Sarcomeres

-Smallest functional unit of the muscle fibre

-Consist of actin and myosin

-Arranged in series

Actin

-Thin Filament

Myosin

-Thick Filament

Excitation-Contraction Coupling

1. Endplate triggers AP

2. AP travels into the muscle via T-tubules

3. Release of Ca2+ form the SR

4. Interaction of Actin & Myosin

*process by which muscle AP (excitation) leads to muscle fiber contraction (contraction)

T-Tubules

-Part of the sarcolemma and wrap around groups of myofibrils

-They are invaginations of the sarcolemma allowing the AP to spread quickly to all

Fasicle

-Bundle of muscle fibers

Ca2+

-Key to muscle contraction

-Secondary messenger from AP to muscle contraction

-Muscle contraction is dependent on its release from the SR

Sliding Filament Theory

1. Myosin head is in a "cocked" position with ATP present

2. Ca2+ reveals binding site on actin which allows myosin head to bind with actin (cross-bridge)

3. Powerstroke - myosin pulls actin towards the centre of the sarcomere

4. While ATP is present:

*Myosin dissociates from actin

*myosin head is "re-cocked"

*Myosin binds to the next active site (if Ca2+ is still present)

5. Cross bridge cycling

Powerstroke

-Myosin pulls actin towards the center of the sarcomere

Muscle Relaxation

-Occurs when stimulation of the motor neuron stops or ATP is no longer available

-Ca2+ is pumped back into the SR, breaking the link between actin and myosin

Muscle Contraction Force

-The amount of force (tension) a muscle can generate is dependent on 6 factors

What are the 6 factors Muscle Contraction Force depend on?

1. Muscle Length

2. Muscle Velocity and direction

3. Innervation ratio

4. Motor Unit Types

5. Size principle

6. Rate Coding

Muscle Length

-The force produced by a muscle varies with this

-Active contraction and passive structures contribute to the total tension in the muscle

-The total tension increases as muscle is lengthened

Passive Contribution (muscle length)

-Muscle lengthened without activation

-Weak actin-myosin bonds, connective tissue and titin act like an elastic (resist being lengthened)

-Farther you stretch (beyond its resting length), the more those elastic components resist = increase in tension

-Increased tension with increased length

What does weak actin-myosin bonds mean?

-even without activation (no Ca2+), a small number of cross-bridges can form when the muscle is stretched

-They contribute to passive stiffness

Active Contraction (Muscle Length)

-Smaller force generated when moving away from optimal length during active contraction

-Less actin-myosin overlap

80-120% is the optimal length

Muscle Velocity & Direction (Muscle Contraction Force)

Eccentric > Isometric > Concentric (greatest to least force production)

Concentric (Shortening)

-Less tension (force) with increasing velocity

-Cross-bridges cannot cycle quickly enough

-Myosin heads do not have enough time to attach and pull the actin

Eccentric (lengthening)

-More tension with increasing velocity

-Greater % of cross-bridges remain attached = greater passive contribution

-Ex: Biceps when lowering a weight back down:

-Cross bridges are actively resisting being pulled apart (active) while the non-contractile tissue is also stretching

-The faster you lower the weight, the more the elastic elements are stretched = greater passive tension

Innervation Ratio (Muscle Force)

-The number of muscle fibers innervated by a single motor neuron = differs between muscle type

-Muscle fibre is only synapsed by 1 motor neuron, and muscle fibres of the same motor unit are distributed throughout the full muscle

Higher Innervation Ratio

-Power/force muscles have this

Smaller Innervation Ratio

-Precision muscles have this

Collateral Sprouting

-Increases the innervation ratio

Muscle Fiber/Motor Unit Types (Muscle Force)

1. Slow Motor Units (type 1; S)

2. Fast Fatigue-Resistant Motor Units (Type 2A; FR)

3. Fast Fatigable (Type 2X; FF)

Slow Motor Units (Type 1; S)

-Small muscle fibers

-Sustained muscular contraction

-Fatigue resistant

-Low threshold for activation (activated first)

Fast Fatigue Resistant Motor Units (Type 2A; FR)

-Medium sized muscle fibres

-Contract less quickly than type 2X

-Generate larger forces

-Fatigue resistant

Fast Fatigable (Type 2X; FF)

-Large muscle fibers that contract quickly

-Generate larger forces

-Easily fatigued

-High activation threshold (activated last)

Size Principle of Motor Unit Recruitment (Muscle Force)

-With increasing levels of motor activation, motor units are recruited from smallest to largest

-Adding more motor units to increase force

S --> FR --> FF

Rate Coding (Muscle Contraction Force)

-Motor unit firing rate

-Smaller muscles rely on this while larger muscle rely more on size principle for recruitment

-increasing force of already active motor units

Single Twitch

-Brief contraction of a muscle fiber in response to one AP

-Contraction is short and weak

Tetanus

-Smooth, sustained contraction due to rapid, repeated APs

-Multiple APs arrive before the muscle has time to relax

Impact of Aging on Neuromuscular Function

-Muscle Fibers decrease in size and number

-Fiber type transformation (fast MU's are converting to slow MUs = decrease in power activities)

-Myofilaments

-Mitochondria

-Adipocyte infiltration

-Excitation-Contraction Coupling

-Satellite Cells

Myofilaments (impact of aging)

-Reduced single fiber maximal force

-Reduction in myosin protein content and function

-Reduction in elasticity

Mitochondria

-Reduced number

-Loss of enzyme content

*less able to be fatigue-resistant

Adipocyte Infiltration

-Increased inter and intra muscular adipose tissue

Excitation-contraction coupling (impact of muscle aging)

-Disruption or uncoupling (loss of synchrony)

-Deficits in Ca2+ release

Satellite Cells

-Reduced number

-Less response to injury

*skeletal muscle regeneration is reduced which can be associated with sarcopenia (loss of muscle mass and function)

What happens to action potential propagation along alpha motor neuron axons as people age?

-Slowed along the alpha motor neuron axons

How does aging affect the density of active areas in the presynaptic terminal?

-Reduced, leading to weaker neurotransmission at the NMJ

What is the effect of aging on motor units?

-There is a loss (but increased size of remaining ones) due to collateral sprouting

What mechanism helps compensate for the loss of motor units during aging?

Collateral sprouting --> surviving neurons grow new branches to reinnervate orphaned muscle fibers

How are neuromuscular junction changes and muscle decline related?

-They are causally linked meaning that changes can cause muscle loss and reduced function with age

ALS and Neuromuscular Function

-It affects specific motor pools and types of motor units

-Rapid loss of fast fatigable neurons, followed by loss of fast fatigue resistant neurons

-Sparing of type 1 neurons

-Loss of strength and power

Stroke and Neuromuscular Function

-Loss of motor units on paretic side

-Smaller muscle CSA

-Reduced ability to use size principle

Spinal Cord Injury and Neuromuscular Function

-Extensive atrophy which moreso affects type 2 fibres esp in Complete > Incomplete

-Transformation towards Type 2X fibres in most pts

-Loss of motor units (50-90%), but lots of collateral sprouting

How are Aging and ALS Different to SCI in terms of Neuromuscular Function?

-There is transformation towards type 2X fibres as opposed to type 1 fibers

Parkinson Disease and Neuromuscular Function

-Loss of motor units (moreso of type 2 motor units)

-Compenesatory type 1 muscle fibre hypertrophy

-Loss of strength and power