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Powell - Muscle 1

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What are the four essential functions of muscle?
Maintain body posture

Stabilize joints

Produce movement

Generate heat
How is skeletal muscle organized?
It is composed of CT, muscle fasicles, nerves, and blood vessels

The muscle fasicles are composed of individual muscle fibers (cells)

A fiber is divided into sarcolemma, T-tubules, sarcoplasm, and multiple nuclei

The sarcoplasm contains the sarcoplasmic reticulum, myofibrils, mitochondria, and glycogen granules

Myofibrils are composed of actin, troponin, tropomyosin, myosin, titin, and nebulin which organize to form a sarcomere
What is the function of the T-tubules?
Bring action potentials into the interior of the muscle fiber
What is the function of the sarcoplasmic reticulum?
To store Ca2+
What is the structure of a myosin (thick) filament?
6 polypeptide chains – 2 heavy chains & 4 light chains

2 Heavy chains: a-helical structure (double helix) – coil around each other as a “tail”

4 Light chains: found in 2 globular heads (cross-bridges)

Filament made of >200 myosin molecules
What is the structure of the actin (thin) filament in muscle?
Composed of 3 proteins: actin, tropomyosin, troponin

1) G-Actin: Globular protein - polymerized into double-stranded helical filamentous actin (F-Actin)

2) Tropomyosin: Filamentous protein that blocks the myosin-binding sites on actin

3) Troponin: Complex of 3 globular proteins: T, I, C
i) Troponin T: Attaches troponin complex to tropomyosin

ii) Troponin I: Inhibits interaction of filaments - covers myosin binding site

iii) Troponin C: Ca+2 binding protein for initiation of contraction
How does the troponin-tropomyosin complex affect muscle contraction?
It has an inhibitory affect on contraction
How are the thick and thin filaments arranged in muscle?
Sarcomere: Basic contractile unit – delineated by Z disks; contains full A band and ½ an I band on either side of A band

A band: contain thick filaments; overlapping of thick and thin filaments potential sites of cross-bridge formation

I band: Contain actin (thin) filaments, Z disks…no thick filaments

Z disk: Run down middle of each I band defining the end of each sarcomere

H (Bare) zone: Center of each sarcomere…No thin filaments thus no overlap of thick and thin filaments/cross-bridge formation in this region

M line: Bisects the H zone linking the central portion of the thick filaments together
What are the different components of each band/zone in a sarcomere?
I band - thin filaments only

H zone - thick filaments only

M line - thick filaments linked with accessory proteins

outer edge of A band - thin and thick filaments overlap
Explain the sliding filament model of contraction
The thin actin filaments (attached to the Z-line) slide inward along the thick myosin filaments, and the sarcomere is shortened.

Note on the measuring scale that as contraction is occurring, both the sarcomere length and the I band length decrease, but the A band length remains constant.

H zone and I band decrease length (the reason why the sarcomere is shorter) but the A band length does not change
What is the role of nebulin?
It helps align actin in the thin filaments
What is the role of titin?
It provides elasticity and stabilizes myosin
What are the basics of muscular dystrophy?
Inherited fatal muscle wasting disease affects mainly boys and leads to their death before the age of 20

Most common form is Duchenne Muscular Dystrophy (DMD)

Causes: Sex-linked disorder passed on the X chromosome from mother or spontaneous mutations on the X chromosome before or during conception that results in defective or absent dystrophin protein
What are the symptoms and treatment of muscular dystrophy?
Clinical manifestations:
Progressive muscle weakness over years beginning at 2-3 years of age (immobility and confinement to wheelchair by age 10-12)

Clumsiness, waddling gait, frequent falls in toddlers

Skeletal deformity; curvature of spine (kyphoscoliosis)

Mental retardation

Frequent respiratory infections and heart failure – death in 20s or younger

No cure: support groups; family counseling; non-strenuous exercises to maintain mobility and function
What is the importance of Ca2+ in cross-bridge cycling?
Ca+2 binds to TnC producing a conformational change in troponin complex. This change moves tropomyosin out of the way allowing binding of actin to myosin heads
What are the molecular basics of muscle contraction?
1) tight binding in the rigor state. The cross-bridge is at a 45 degree angle relative to the filaments

2) ATP binds to the binding site on myosin. Myosin then dissociates from actin

3) The ATPase activity of myosin hydrolyzes the ATP.ADP and Pi remain bound to myosin

4) The myosin head swings over and binds weakly to a new actin molecule. The cross-bridge is now at 90 degrees relative to the filaments

5) Release of Pi initiates the power stroke. The myosin head rotates on its hinge, pushing the actin filament past it

6) At the end of the power stroke, the myosin head releases ADP and resumes the tightly bound rigor state (step 1)
Explain the details of muscle contraction at the molecular level
A.At the beginning of cycle – no ATP is bound to myosin - myosin is tightly attached to actin in a “rigor” position

B. Binding of ATP to a cleft on the back of myosin head produces a conformational change in myosin decreasing its affinity for actin- so myosin is released from the actin binding-site

C.Cleft closes around the bound ATP molecule - a further conformational change causing myosin to be displaced toward the + end of actin. ATP is hydrolyzed (by myosin ATPase) to ADP and Pi, which remains attached to myosin

D. Myosin binds to a new actin site (closer to + end) constituting the force- generating or power stroke. Each cross-bridge “walks” the myosin head 10 nm

E. Once the head of the cross-bridge tilts, ADP is released and myosin returns to its original state with no nucleotides bound (A).

Cross bridge cycling continues with myosin“walking” to + end of actin filament
What is the Fenn effect?
The greater the amount of work by muscle, the greater the amount of ATP cleaved
What is the cross-bridge activity during contraction?
1) binding - myosin cross-bridge binds to actin

2) power stroke - cross-bridge bends, pulling thin filament inward

3) cross-bridge detaches at the end of power stroke and returns to original conformation

4) cross-bridge binds to more distal actin molecule, cycle repeated
Explain rigor mortis
Stiffening or contraction of muscle that occurs several hours 3-4 hours after death

Results from ATP depletion in muscle cells

Peak rigidity occurs at 12 hours as a result of:
a) Inability of the dying cells to remove calcium

b) Calcium influx into muscle cells promotes binding of myosin cross bridges

c) No ATP available to bind myosin for cross bridge detachment

d) Actin and myosin become irreversibly cross-linked and crossbridges remain contracted

Within a day (48-60 hours) muscle proteins are destroyed by local enzymes released as cells degenerate, causing muscles to relax
What is the sequence of events in skeletal muscle excitation-contraction coupling?
1)Action potential in skeletal muscle fiber

2)The rise in intracellular free [Ca+2]

3)Contraction of muscle fiber

Cytoplasmic [Ca+2] controls strength and duration of
What is the general mechanism that leads to muscle contraction?
1) ACh binds to ACh receptors on motor end plate

2) Action potential caused by end plate potential is propagated across the surface membrane and down the T-tubules

3) Action potential triggers Ca2+ release from the sarcoplasmic reticulum

4) Ca2+ ions bind to troponin on actin filaments; tropomyosin is physically moved aside to uncover the cross-bridge binding sites

5) myosin cross-bridges attach to actin and bend, pulling actin filaments toward center of sarcomere; powered by ATP

6) Ca2+ actively taken up by sarcoplasmic reticulum when there is no more action potential

7) Without Ca2+ present, tropomyosin slides back to its blocking position over actin; contraction ends and actin slides back into its resting position
What are the two types of muscular contractions?
2 types of muscular contractions:

Isometric Contraction: Muscle is allowed to develop tension but is not allowed to shorten; since muscle cannot shorten to lift object remains at constant length despite tension development

Isotonic Contraction: A contraction in which the muscle shortens while pulling a constant load (afterload); weight of object unchanged so muscle tension remains constant
Explain isomeric contraction
An isometric contraction is a contraction in which the muscle length remains constant as the tension in the muscle increases.

Cross-bridge formation between actin and myosin increases the tension. However, the tension produced never exceeds the resistance it’s working against so muscle never shortens.

Although cross-bridges form and tension rises to peak values, the muscle cannot overcome the resistance of the weight and so cannot shorten (hence no sliding of filaments).
Explain isotonic contraction
An isotonic contraction refers to muscle contraction during which cross-bridge formation and cycling between cross-bridges is leading to the shortening of the muscle with constant tension.

Before the muscle can shorten, the cross-bridges must produce enough tension to overcome the resistance. Over this period, tension in the muscle fibers rises until it exceeds the amount of resistance. As the muscle shortens, the tension in the muscle remains constant at a value that just exceeds the resistance
How do isotonic and isometric contraction work together?
In reality, when a muscle contracts in vivo its contraction is usually a mixture of isometric and isotonic contraction,

ex - when lifting a weight, a muscle must first develop enough tension to exceed that of the weight alone (isometric) before it can actually shorten (isotonic).

ex - picking up a book to read, biceps undergoes an isotonic contraction while lifting the book but contraction becomes isometric as you stop to hold the book in front of you.
Explain the length-tension relationship
Length-Tension Relationship: Amount of tension a muscle generates depending on how stretched it is before it is stimulated to contract

Amount of tension is determined for isometric contractions (muscle develops tension at resting length (preload) but cannot shorten i.e. 500 lb barbell)

3 measurements of tension that can be made as a function of resting length (preload)
Passive tension
Active tension
Total tension
Explain active and passive tension
Passive: Tension developed by stretching muscle to different lengths

Active: Active force developed when muscle contracts


Total (active + passive): Tension when muscle is stimulated to contract at different pre-loads
Explain the force-velocity relationship in contraction
Speed of shortening depending on afterload against which muscle must contract

Determined by allowing muscle to shorten - isotonic contraction

Small loads – shortens faster
Large loads – shortens slower
NO LOAD – shortens quickest
regardless of muscle length (Vmax)

Maximal velocity (afterload = 0) depends on fiber type

If load = max force muscle can exert, velocity of shortening = 0 (no contraction – isometric
Explain twitch, twitch summation, and tetanus
If a muscle fiber is restimulated after it has completely relaxed, the second twitch is the same magnitude as the first twitch

If a muscle fiber is restimulated before it has completely relaxed, the second twitch is added on to the first twitch, resulting in summation

If a muscle fiber is stimulated so rapidly that it has no chance to relax at all between stimuli then a maximal sustained contraction known as tetanus occurs
How does cytosolic Ca2+ relate to muscle contraction?
Increase in tension reflects accumulation of Ca+2 in the cytosol

Major mechanism for adjusting strength of contraction in skeletal muscle: Adjust frequency of action potentials traveling down a motor neurons to muscle fibers
What are the basics of motor units?
Motor unit: A single a-motorneuron and all the muscle fibers it enervates

Number of muscle fibers in a motor unit determines:
a. Maximal strength of contraction
b. Minimal increment of tension contributed by unit

Small motor units - fewer muscle fibers per motor unit (~2-3) (fine control)

Large motor units - 1000s of muscle fibers in a motor unit (powerful, coarse control)
What does tension generated by a skeletal muscle depend on?
1.Properties of individual muscle fibers:

Slow oxidative (type I)
Fast oxidative-glycolytic (type IIa)
Fast glycolytic (type IIb)

2. Properties of motor units

3.Recruitment of motor units
What are the different muscle fiber types and how do they relate to function?
Type I: slow oxidative

Type IIa: fast oxidative-glycolytic

Type IIb: fast glycolytic

Types of fibers found in a muscle support its function – fast fibers adapted for rapid POWERFUL muscle contractions (arm muscles- lifting); slow fibers adapted for slow PROLONGED muscle activity (back and legs that support the body’s weight against force of gravity

more ex's -
Ocular muscles are fast and type II fibers predominate

Soleus is a slow and continuously active anti-gravity muscle with type I fibers predominating
How are the muscle fibers classified?
Fiber type based on differences in ATP hydrolysis and synthesis dictating speed of contraction (slow or fast) and enzymatic machinery primarily used for ATP formation (oxidative or glycolytic)
What are the different ways to increase the speed and strength of muscle contractions?
Increase amount of Ca+2

Change the length of muscle fibers

Change the frequency of stimulation (intracellular Ca+2)

Size of muscle fibers (hypertrophy)

Number of muscle fibers in motor unit (hyperplasia)

Recruitment of motor units
What are the three metabolic systems that supply ATP energy for muscle contraction?
1. Phosphocreatine - transfer of hi-energy P from creatine-P to ADP

2. Glycogen to pyruvate to lactic acid (glycogenolysis and glycolysis is the main source when oxygen is lacking)

3. oxidation of glucose, fatty acids and amino acids - aerobic metabolism, oxidative phosphorylation; main source when oxygen is present
What are the contributions of the different metabolic pathways (contraction) during exercise?
Phosphate: Limited amount used in first few seconds of exercise (8-10 seconds)

Anaerobic metabolism: Glycogen is broken down during heavy exercise; lactic acid produced (1.3 to 1.6 minutes)

Aerobic metabolism: Nutrient breakdown - with extra long exercise, cardiovascular and respiratory adjustments are made - becomes dominant (unlimited time as long as nutrients last)
What is rhabdomyolysis?
Rhabdomyolysis is the rapid breakdown (lysis) of skeletal muscle tissue (rhabdomyo) due to injury to muscle tissue.

The muscle damage may be caused by physical (e.g. crush injury), chemical, or biological factors.

The destruction of the muscle leads to the release of the breakdown products of damaged muscle cells into the bloodstream; some of these, such as myoglobin, are harmful to the kidney and may lead to acute kidney failure.

Treatment is with intravenous fluids, and dialysis or hemofiltration if necessary
Explain the concept of oxygen debt
2 L of stored O2 that can be used for aerobic metabolism without new O2 (lungs, body fluids, Hb, muscle fibers)

All O2 used within a minute for aerobic metabolism – must be restored by taking in extra O2 above normal amounts

Extra 9 L needed to replenish phosphagen system (cell ATP and Creatine-P) and lactic acid system

Extra O2 that must be repaid = 11.5 L = O2 DEBT
How is oxygen debt re-paid?
After exercise is finished O2 uptake is very high while body is repaying the stored O2 and reconstituting ATP and CP stores (Early portion of O2 debt is Alactacid O2 debt = 3.5L AND for another 40 minutes at a lower level removal of lactic acid (Later portion of O2 debt is lactic acid O2 debt = 8L)
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