1. Frontal lobe: encodes and manipulates action memories

Ventral

Dorsal

or crossover

• A single skeletal muscle cell is called muscle fiber (MF) – electrically continuous inside, – electrically isolated from outside

• Each MF is formed during development by the fusion of a number of undifferentiated mononucleated cells, known as myoblasts

• Myoblasts fuse into multinucleated cylindrical MF; completed by around the time of birth

• Single MF is 10µm to 300µm in diameter and may extend up to 30cm in length (whole length of biceps muscle) and contain >1,000 nuclei

• DEFINITION: muscle is a number of MFs bound together by connective tissue (collagen)

• Muscles are connected to bones by tendons (triple helix of protein collagen* - stronger than steel of the same diameter)

• Tendons can be very long: some of the muscles that move fingers are located in the forearm**.

• Why finger muscles are away from the hand?

One cell =

• What is the relationship between a motor neuron and muscle fibers? A. one motor neuron innervates one muscle fiberB. several motor neurons innervate one muscle fiberC. one motor neuron innervates two or three muscle fibersD. one motor neuron innervates around 100 muscle fibers

Ventral root

• Definition: Motor unit = motor neuron and MFs it controls (usually several hundred MFs)

• Motor unit 1 = motor neuron 1 and blue MFs

• Motor unit 2 = motor neuron 2 and red MFs

• The muscle fibers of a motor unit are dispersed randomly within the area of the muscle and fibers innervated by the same motor neuron are not contiguous

The number of motor units vary greatly among muscles:

• 10 in extraocular muscles• 100 in intrinsic muscles of the hand• 5,000 in leg muscle

The number of muscle fibers (cells) per muscle:

• 1000 MFs in extraocular muscles(1000 MF / 10 motor units 100 MF in one motor unit)

• 1,000,000 MF in large leg muscle(1,000,000 MFs / 5,000 motor units 200 MFs in one motor unit)

The strength of muscle contraction depends on:1. The number of motor units recruited2. The frequency of motor unit discharge3. The speed of contraction of muscle fibers in

the motor unit4. The nature of motor unit (whether it is

fatigue-resistant or fatigue –prone)

Contraction duration:• Snail muscle contraction can last for 1

second• Honey bee contraction lasts for 3

millisecond (300 twitches / second)

In all skeletal muscles:• Contractile elements: Actin, myosin• ATP provides energy• Increase in calcium concentration triggers

contraction

Single cell (electrically isolated)

Sarcomere

• Sarcomere (Greek: sarco- (“flesh”) + -mere (“component”))• Sarcomere shortens during contraction like a collapsing telescope• Stack many sarcomeres together longitudinally myofibril• A single myofibril has the length of a muscle fiber

2um

1um

• Muscle fibers look striated under the light microscope

Inside a sarcomere

Myosin = thick filament

Actin= thin filamentActin is attached to Z-line discs

Actin is attached to Z-line discs

Myosin is suspended by titin

titin

Z-lin

e di

sc

Myosin cross-bridges pulling on the actin

• three sarcomeres stuck longitudinally

• sarcomere cross section

Range of sarcomere contraction

Cannot contract any further No tension

Range of sarcomere contraction

Cannot form crossbridges No tension

Fibroblast labeled with probes for actin and the nucleus. The actin of cytoskeleton is visualized

actin

Actin is found in a any cell

• Myosin head interacts with actin

• Hydrolyzes ATP

120nmCalcium binding protein

Tropomyosin is held in place by Troponin

Myosin head • Myosin tails bind

together to form the thick filament

1. Actin (A) bound to myosin (M):A· M

2. Binding of ATP dissociates myosin:

A· M + ATP A + M· ATPfast reaction

4. Cross-bridge binds to actin, now ADP and Pi can be released:

A + M · ADP · Pi A · M · ADP · Pi

3. ATP hydrolysis to ADP and Pi energizes myosin:

A + M· ATP A + M · ADP · Pi

fast reaction

5. As soon as ADP + Pi are released, the head region is glad to bend back

and pulls actin filaments: A · M · ADP · Pi A · M + ADP + Pi

Cross-bridge cycle in 5 frames

1. Actin (A) bound to myosin (M):A· M

Muscle is stiff. Few hour after death no ATP Rigor mortis

(Lat. Stiff death)

2. Binding of ATP dissociates myosin:

A· M + ATP A + M· ATPMuscle is flexible

3. ATP hydrolysis to ADP and Pi energizes myosin:

A + M· ATP A + M · ADP · Pi

this myosin head position is unstable. It wants to bend back, but it cannot until it releases ADP and Pi. Without binding to actin, myosin releases ADP and Pi very slowly: half life is 14 seconds Even at rest muscle continues to burn ATPs producing heat

4. Cross-bridge binds to actin

5. As soon as ADP + Pi

are released, the head region is glad to bend back and pulls actin

Two distinct roles of ATP in cross-bridge cycle

1. The energy released by ATP hydrolysis provides the energy for cross-bridge movement.

2. The binding of ATP to Myosin allows Myosin to dissociate from actin– Several hours after death ATP concentration

decreases skeletal muscle become stiff (Rigor mortis)

– The stiffness disappears in 48h to 60h after death as a result of disintegration of muscle tissue

• Only 50% of cross-bridges are bound at any moment• One stroke of cross-bridge produces only a very small movement

(~10nm)• As long as muscle remains ‘on’ cross-bridges repeat their

swiveling motion• What keeps muscle from continuous contractile activity?

32

What keeps muscle from continuous contractile activity?

Tropomyosin is held by Troponin in resting muscle in the position that does not allow myosin to bind to actin

• Muscle tension is a function calcium concentration

Mus

cle

tens

ion

Calcium concentration100nM 1µM 10µM

Excitation-contraction coupling

• Where does calcium come from?

1. Motor neuron action potential

-80mV

+30mV

4. Calcium concentration inside

5. Muscle tension(one twitch)

3. Muscle fiber action potential is conducted from neuromuscular junction located in the middle of a fiber to both ends of a muscle fiber

+30mV

EPSP-90mV

2. EPSP is amplified Muscle fiber action potentialDepolarization produced by influx of Na (through ACh channels) is amplified by muscle’s own voltage-activated channels

Where does calcium come from in a neuron?

• From ECF. • Since concentration gradient is huge (1mM outside vs. 0.0001mM

inside), it is enough to just open calcium channels calcium will be pouring into the axonal terminal

1µm

300µ

m

Axon terminals are small (1µm) and muscle fibers are huge (up to 300µm) it would take forever for calcium from ECF to diffuse to central myofibrils

Solution surround each myofibril with calcium storage

• AP opens calcium channels on SC• After AP calcium is sucked away by a number of ATP driven pumps (30,000 pumps/ µm2 )

1µm

300µ

m

How to transmit AP to all s. reticula simultaneously?Solution T-tubules (local plumbing) - electrically continuous with ECF, just like power lines in a house are used to transmit electricity

Temporal summation and Tetanus

• Maximum tension that this muscle can produce under this length

isometric contraction == constant length

• In a lab we can manipulate muscle length measure maximum tension developed by the muscle at that length

isometric contraction == constant length

• Conclusion: there is some optimal length at which the developed tension is maximal

• mechanism - • consider myosin and actin arrangement:

isometric contraction == constant length

• In the body muscles are very close to optimal length (a) in the extended state.

• Bones prevent muscles from extending beyond this length

isometric contraction == constant length

• How much muscle will shorten with the weight of 50 gram

• With a load of 50gram this muscle will only shorten to E

• each sarcomere will shorten by 0.5µm (from 2.1µm to 1.6µm)

isotonic contraction == constant load

(gra

m)

E

50 gram

50 gram

Types of skeletal muscles

Two types of tasks:– Some tasks involve continuous muscle activity (tonus, walking) muscles are not allowed to fatigue. Movements involved in these tasks are usually slow.

– Other tasks normally last only short time (running away from a predator). The movements involved in these tasks are usually fast.

To address these two very different tasks, we have two different types of muscles fibers:– slow MF that never fatigue: you can walk for 2 miles (using

slow muscles) without getting tired– fast MF that fatigue quickly: if you run two miles (using fast

muscles, you will be very tired)

Contraction velocity Slow (Type I) Fast (Type IIx)

Rate of fatigue never quickly

Why fast/slow? Myosin ATPase activity is slow (slowly split ATP) Myosin ATPase activity is fast (split ATP fast)

Source of ATP production Oxidative phosphorylation (aerobic) Glycolysis (anaerobic)Mitochondria Many Few

Myoglobin content High (red muscle) Low (white muscle)Fiber diameter small large

Motor unit size small large

Capillaries around MF Large number of capillaries Few capillaries

Motor unit firing rate Continuously at a low rate High firing rate

Athletes Extreme endurance athletes World-class sprinter

Tension

300ms 30ms

fine control by slow MF

gross control by fast MF

time

twitch waveform

Find the slow-twitch MF, fast?fast MF (big and white)

slow MF (small and red)

Sensors

• Close your eyes move your hand forward, back

• How do you know the position of the muscles?

• Two types of sensors:• Length sensors inside

the muscle: muscle spindle

• Tension sensors: Golgi tension organ

Golgi tendon organ

• How sensory information is encoded by neurons?• Information is encoded in frequency of action

potentials (firing frequency = number of action potentials per second)

• How motor information is encoded by a motor neuron?• Again, information is encoded in frequency of action potentials: the

greater the firing rate the greater the tension• What is the range of firing rate?• Is every motor neuron action potential followed by a muscle

contraction?• In addition CNS can recruit more motor units

Amyotrophic lateral sclerosis • Also known as Charcot disease, Lou Gehrig's disease

in US and motor neuron disease in UK.• Lou Gehrig (1903 – 1941) was a baseball player who

played 17 for the New York Yankees, from 1923 through 1939. In 1939 he was diagnosed with ALS and died two years later.

• ALS is characterized by gradually worsening muscle weakness. This results in difficulty speaking, swallowing, and eventually breathing.

• The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-rich inclusions in their cell bodies and axons.

• In 90% of case the cause is unknown. In 10% ALS is due to inherited mutation.

• Stop here