Copyright © 2006 by Elsevier, Inc. “Walk-Along” Theory Figure 6-7; Guyton & Hall.

Copyright © 2006 by Elsevier, Inc.

“Walk-Along” Theory

Figure 6-7; Guyton & Hall

U N I T II

Textbook of Medical Physiology, 11th Edition

GUYTON & HALL


Chapter 6:Contraction of Skeletal Muscle

Slides by Thomas H. Adair, PhD


Anatomy of Skeletal MuscleGross organization:



Cellular Organization

Muscle fibers• single cells• multinucleated• surrounded by the sarcolemma

Myofibrils• contractile elements• surrounded by the sarcoplasm

Cellular organelles - lie between myofibrils (mitochondria, sarcoplasmic reticulum etc.) Figure 6-1; Guyton & Hall


Molecular Organization



The Sarcomere

A band

I bandZ disc

sarcomere

thick filament (myosin)

thin filament (actin)

titin (filamentous structural protein)

M line

H zone


“Sliding Filament” Mechanism

Contraction results from the sliding action of interdigitating actin and myosin filaments

RELAXED:

CONTRACTED:


F-actin • double-stranded helix• composed of polymerized G-actin • ADP bound to each G-actin (active sites)• myosin heads bind to active sites

tropomyosin • covers active sites• prevents interaction with myosin

troponin • I - binds actin• T - binds tropomyosin• C - binds Ca2+

The Actin Filament

− the I band filament− tethered at one end at the Z disc− 1 m long: v. uniform nebulin forms guide for synthesis



The Myosin Molecule:

• two heavy chains (MW 200,000)• four light chains (MW 20,000) • “head” region - site of ATPase activity



Mechanism of Muscle Contraction

Theory: Binding of Ca2+ to troponin results in a conformational change in tropomyosin that “uncovers” the active sites on the actin molecule, allowing for myosin to bind.


“Sliding Filament” Mechanism

Contraction results from the sliding action of interdigitating actin and myosin filaments

RELAXED:

CONTRACTED:


Neuromuscular Transmission- The Neuromuscular Junction -

• Specialized synapse between a motoneuron and a muscle fiber• Occurs at a structure on the muscle fiber called the motor end plate (usually only one per fiber)



Synaptic trough: invagination in the motor endplate membrane

• Synaptic cleft: − 20-30 nm wide− contains large quantities of acetylcholinesterase (AChE)

• Subneural clefts: − increase the surface area of the post-synaptic membrane− Ach gated channels at tops− Voltage gated Na+ channel in bottom half

Neuromuscular Junction (nmj)



The Motoneuron – vesicle formation

• Synaptic vesicles: are formed from budding Golgi and are transported to the terminal by axoplasm “streaming” (~300,000 per terminal)

• Acetylcholine (ACh) is formed in the cytoplasm and is transported into the vesicles (~10,000 per)

• Ach filled vesicles occasionally fuse with the post-synaptic membrane and release their contents. This causes miniature end-plate potentials in the post-synaptic membrane.


The Motoneuron - ACh Release

Ca2+

1. AP begins in the ventral horn of spinal cord.

2. Local depolarization opens voltage-gated Ca2+ channels.

3. An increase in cytosolic Ca2+ triggers the fusion of ~125 synaptic vesicles with the pre-synaptic membrane and release of ACh (exocytosis).

AP1

3

2


• Ca2+ channels are localized around linear structures on the pre-synaptic membrane called dense bars.

• Vesicles fuse with the membrane in the region of the dense bars.

ACh Release - details

• Ach receptors located at top of subneural cleft.

• Voltage gated Na+ channels in bottom half of subneural cleft.



End Plate Potential and Action Potential

• Opening of nACh receptor channels produces an end plate potential, which will normally initiate an AP if the local spread of current is sufficient to open voltage sodium channels.

40

0

-40

-80

mV

0 15 30 45 60

75 mSec

nAChrNa channel

• ACh released into the neuromuscular junction binds to, and opens, nicotinic ACh receptor channels on the muscle fiber membranes (Na+, K+, Ca2+).

• What terminates the process?

- at the motor endplate -

acetylcholinesterase


Curariform drugs (D-turbocurarine)

• block nicotinic ACh channels by competing for ACh binding site

• reduces amplitude of end plate potential therefore, no AP

Botulinum toxin• decreases the release of Ach from nerve terminals• insufficient stimulus to initiate an AP

Drug Effects on End Plate Potential - Inhibitors -

“normal”

curare botulinum toxin

threshold



ACh-like drugs (methacholine, carbachol, nicotine)• bind and activate nicotinic ACh receptors• not destroyed by AChE – prolonged effect

Anti-AChE (neostigmine, physostigmine, diisopropyl fluorophosphate or “nerve gas”)

• block the degradation of ACh• prolong its effect

Drug Effects on End Plate Potential

- Stimulants -


Myasthenia Gravis

Incidence / symptoms:

Cause:

Treatment: • usually ameliorated by anti-AChE (neostigmine)• increases amount of ACh in nmj

• paralysis - lethal in extreme cases when respiratory muscles are involved • 2 per 1,000,000 people / year

• autoimmune disease characterized by the presence of antibodies against the nicotinic ACh receptor which destroys them• weak end plate potentials


Lambert-Eaton Myasthenic Syndrome

Incidence / symptoms:

Cause:

Treatment: • can be treated with anti-AChE (neostigmine)• increases amount of ACh in nmj

• 1 per 100,000 people / year• 40% also have small cell lung cancer • muscle weakness/paralysis

• LEMS results from an autoimmune attack against voltage-gated

calcium channels on the presynaptic motor nerve terminal. • weak end plate potentials


Excitation-Contraction CouplingTransverse tubule / SR System

T-tubules:• Invaginations of the sarcolemma filled with extracellular fluid• Penetrate the muscle fiber, branch and form networks• Transmit AP’s deep into the muscle fiber

Sarcoplasmic Reticulum:• terminal cisternae and longitudinal tubules • terminal cisternae form junctional “feet” adjacent to the T- tubule membrane• intracellular storage compartment for Ca2+



Arrangement of T-tubules to Myofibrils

Vertebrate skeletal muscle:• Two T-tubule networks per sarcomere• Located near the ends of the myosin filaments (zone of overlap)

Cardiac muscle (and lower animals):• Single T-tubule network per sarcomere• Located at the level of the Z disc

- Skeletal muscle vs cardiac muscle -



EC Coupling - the “Triad”• the junction between two terminal cisternae and a T-tubule

T-tubule

dihydropyridinereceptor: it’s a voltage sensor

ryanodine Ca2+ release channel

Terminal cisterne of SR


EC Coupling – how it works (skeletal muscle)

AP

Ca2+ pump

calsequestrin

Sequence of Events:1. AP moves along T-tubule2. The voltage change is sensed

by the DHP receptor.3. Is communicated to the

ryanodine receptor which opens. (VACR)

4. Contraction occurs.5. Calcium is pumped back into

SR. Calcium binds to calsequestrin to facilitate storage.

6. Contraction is terminated.


Clinical Oddity: Malignant Hyperthermia

• triggered by anesthetics (halothane)• familial tendency - can be tested for by muscle biopsy• constant leak of SR Ca2+ through ryanodine receptor

Cause:

• spontaneous combustion • skeletal muscle rigidity• lactic acidosis (hypermetabolism)

Symptoms:

Ca pump

ATP

Our bodies are only about 45% energy efficient. 55% of the energy appears as heat.

Why is so much heat

generated?


Muscle Mechanics


Normal operating range

Tension as a Function of Sarcomere Length

• Stress is used to compare tension (force) generated by different sized

muscles

– stress = force/cross-sectional area of muscle; units kg/cm2)

• In skeletal muscle, maximal active stress is developed at normal resting length ~ 2 m

• At longer lengths, stress declines -

• At shorter lengths stress also declines -

• Cardiac muscle normally operates at lengths below optimal length -

activestress(tension)

sarcomere length (m)

0

1

0 1 2 3 4

0.5


Frequency Summation of Twitches and Tetanus

• Myoplasmic Ca2+ falls (initiating relaxation) before development of maximal contractile force

• If the muscle is stimulated before complete relaxation has occurred the new twitch will sum with the previous one etc.

• If action potential frequency is sufficiently high, the individual contractions are not resolved and a ‘fused tetanus’ contraction is recorded.

Myoplasmic [Ca2+]

Force

APTime (1 second)

Fused tetanus


Motor Unit:

• All fibers are same type (fast or slow) in a given motor unit• Small motor units (eg,larnyx, extraocular)

− as few as 10 fibers/unit − precise control− rapid reacting

• Large motor units (eg, quadriceps muscles) − as many as 1000 fibers/unit− coarse control− slower reacting

• Motor units overlap, which provides coordination• Not a good relation between fiber type and size of motor unit

A collection of muscle fibers innervated by a single motor neuron

• large diameter


Relationship of Contraction Velocity to Load

no afterload:• maximum velocity at minimum load

increased afterload:• contraction velocity decreases

contraction velocity is zero when afterload = max force of contraction

A

B

A: larger, faster muscle (white muscle)B: smaller, slower muscle (red muscle)


Types of Skeletal Muscle - speed of twitch contraction -

• Speed of contraction determined by Vmax of myosin ATPase.

– High Vmax (fast, white)

• rapid cross bridge cycling • rapid rate of shortening

(fast fiber)– Low Vmax (slow, red)

• slow cross bridge cycling • slow rate of shortening

(slow fiber)• Most muscles contain both types of

fiber but proportions differ• All fibers in a particular motor unit

will be of the same type i.e., fast or slow.



• fast and slow fibers show different resistance to fatigue

• slow fibers– oxidative

• small diameter• high myoglobin content• high capillary density• many mitochondria• low glycolytic enzyme

content

• fast fibers – glycolyticfo

rce

(% in

itial

)

time (min)50 60

Fast (white muscle)

Slow (red muscle)

Types of Skeletal Muscle- resistance to fatigue -


What do the different types do?

• Fast, slow and intermediate twitch type muscle can be identified by histochemistry.

• In any muscle there will be a mixture of slow and fast fibers.

• Motor units containing slow fibers will be recruited first to power normal contractions.

• Fast fibers help out when particularly forceful contraction is required.

Different people have different proportions of these types.

There is little evidence that training alters these proportions in humans.

Fast-twitch slow-twitch

Marathon 18% 82%Runners

Swimmers 26 74

Average 55 45 man

Weight 55 45Lifters

Sprinters 64 37

Jumpers 63 37


Conversion of Fiber Type - fast to slow -

• Anterior tibialis – – Predominantly fast twitch (upper)– Stains light: few mitochondria – Few, small capillaries– Large fibers

• Electrical stimulation (10 Hz) via motor nerve (60 days)

– Stimulating fast muscle at the pace of a slow muscle converts fast twitch fibers to predominantly slow twitch fibers (lower)

– Stains dark: more mitochondria– Many, large capillaries– Larger fibers

left AT

right AT


Force summation: increase in contraction intensity as a result of the additive effect of individual twitch contractions

(1) Multiple fiber summation: results from an increase in the number of motor units contracting simultaneously (fiber recruitment)

Muscle Contraction - force summation

(2) Frequency summation: results from an increase in the frequency of contraction of a single motor unit



Muscle Remodeling - growth

hyperplasia

hypertrophy

lengthening

• Hypertrophy (common, weeks)– Caused by near maximal force development

(eg. weight lifting)– Increase in actin and myosin– Myofibrils split

• Hyperplasia (rare)– Formation of new muscle fibers– Can be caused by endurance training

• Hypertrophy and hyperplasia– Increased force generation– No change in shortening capacity or

velocity of contraction

• Lengthening (normal) – Occurs with normal growth– No change in force development– Increased shortening capacity – Increased contraction velocity


Muscle Remodeling - atrophy

atrophy with fiber loss

atrophy

• Causes of atrophy– Denervation/neuropathy– Tenotomy– Sedentary life style– Plaster cast– Space flight (zero gravity)

• Muscle performance– Degeneration of contractile proteins– Decreased max force of contraction– Decreased velocity of contraction

• Atrophy with fiber loss– Disuse for 1-2 years– Very difficult to replace lost fibers

weeks

months/years

Date post:	17-Dec-2015
Category:	Documents
Upload:	christine-owen
View:	216 times
Download:	0 times

Copyright © 2006 by Elsevier, Inc. “Walk-Along” Theory Figure 6-7; Guyton & Hall.

Documents