Skeletal Muscle Physiology (Week 1--Homsher)

Question 1

Skeletal muscle fibers

Answer 1

Large diameter (20-100um)

Long (2mm - tens of cm, almost entire length of muscle)

Multi-nucleate

Contain regenerative satellite cells

T-tubules smaller and sarcoplasmic reticulum as much as 7% of cell volume

Much more Ca2+ and calsequestrin in skeletal muscle

Question 2

Costameres

Answer 2

Sub-sarcolemmal protein assemblies that contain desmin (floppy), dystrophin, gamma-actin

Connect and align Z-disk of myfibrils to each other and to dystroglycans and sarcoglycans (integral membrane proteins)

Integral membrane proteins then bind laminin, fibronectin, collagen in ECM

Costameres and dystrophin link contractile proteins and cytoskeleton to ECM and minimize damage to sarcolemma

Question 3

Function of costameres

Answer 3

Links and aligns myofibrils with each other and transmits force and displacement occurring in them to ECM and to adjacent muscle cells

Minimizes disruption of phospholipid layer of sarcolemma when muscle length changes significantly during shortening or lengthening

Question 4

What happens if you have absent or defective dystrophin?

Answer 4

Duchenne Muscular Dystrophy (DMD)

Working muscles damaged when try to undergo concentric and eccentric contraction and make cell membrane leaky to Ca2+ so intracellular proteases activated

Damaged muscle fibers gradually degenerate –> death

Dystrophin located in skeletal and cardiac muscles, brain and lung tissue

Question 5

Duchenne Muscular Dystrophy (DMD)

Answer 5

Absence of or defect in dystrophin

Disease is due to lack of connection of costameres!

X-linked so only affects males (3/10,000 live births)

Working muscles damaged by concentric and eccentric contractions so cell membrane leaky to Ca2+ and intracellular proteases activated, intracellular creatine kinase appears in blood

Muscle fibers damaged faster than repair –> muscle breakdown or infiltration by macrophages, leukocytes, cytotoxic T cells –> apoptosis –> fat globules or fibrous tissue –> children to wheel chair by age 12, death from respiratory or cardiac disease in teens or 20’s

Question 6

Becker Dystrophy

Answer 6

Expression of modified or truncated form of dystrophin and produces slowly progressive dystrophy and less severe symptoms than DMD

Myalgias, muscle cramps, reduced exercise tolerance, mild limb girdle weakness

Question 7

What causes Ca2+ to enter the sarcoplasm in skeletal muscle to trigger contraction?

Answer 7

Depolarization of T-tubules

S4 region (voltage sensing, membrane spanning) of L-type Ca2+ channel (aka DHP receptor) is positively charged and pulls on/opens up Ca2+ pore in RyR in the SR

Ca2+ flows out of SR through RyR

Note: don’t need influx of Ca2+ across sarcolemma to initiate Ca2+ release from SR

Question 8

Cross bridge mechanism

Answer 8

Same as in cardiac muscle but faster (>2x faster)

Question 9

Sliding filament mechanism

Answer 9

SKM contracts and relaxes over a wider sarcomere length range (1.6 - >3um)

Force plateau from 2.25 - 2.55um

Question 10

Calcium regulation of contraction

Answer 10

TnC in SKM contains 2 regulatory Ca2+ binding sites so full activation of SKM requires Ca2+ release at least 2x cardiac muscle

Ca2+ released from SKM SR RyRs by electro-mechanical coupling mechanism (rather than Ca2+-induced Ca2+ release in cardiac muscle)

Question 11

Active vs. passive force

Answer 11

Active force involves cross bridge interaction, splitting ATP

Passive force is just moving muscle

Question 12

Can skeletal muscle cells regenerate?

Answer 12

Yes, use satellite cells (stem cells)

Muscle is damaged all the time, so is important to be able to regenerate!

(this is in contrast to cardiac cells)

Question 13

How do skeletal muscle fibers regenerate?

Answer 13

Fiber injury

Neutrophil invasion, necrosis and autolysis

Macrophage removal of necrotic tissue

Satellite cell mitosis and proliferation

Satellite cell fusion

Fusion to myotube and fusion with fiber stumps

Restoration of original fiber

Question 14

How many muscle fibers does a single alpha-motor neuron innervate?

Answer 14

Number of muscle cells per motor unit is variable (5-2,000 separate muscle fibers)!

However, each AXON of a neuron only innervates ONE muscle fiber

Question 15

Does the size of the motor neuron tell you how many muscle fibers it might innervate?

Answer 15

Yes, smaller motor neurons innervate fewer fibers (thus make smaller force) and larger motor neurons innervate more muscle fibers (thus make larger force)

Also means smaller current needed to initiate AP in smaller motor neuron, and larger current needed in larger motor neuron

Question 16

How do motor neurons initiate muscle contraction?

Answer 16

Alpha-motor neuron starts in ventral horn of gray matter of spinal cord

Efferent myelinated axon to muscle fibers motor endplate

At motor endplate (highly folded series of clefts or grooved region of muscle sarcolemma), synapse where ACh released by axon terminal onto nicotinic receptors of muscle membrane

Sarcolemmal conductance to Na+ and K+ increased and membrane potential increases/depolarizes

Initiates AP in membrane adjacent to endplate by passive conduction

AP spreads over entire muscle cell membrane

Neuromuscular cleft contains lots of AChE so ACh is hydrolyzed so AP at NM junction and AP generated by muscle membrane is 1:1

Question 17

Does the SKM action potential overshoot and have a hyperpolarization phase?

Answer 17

No! It actually “undershoots” to a value more positive than resting potential then gradually returns to resting potential

Question 18

Latent period

Answer 18

5-18ms delay between beginning of muscle AP and beginning of force development

During this time, excitation-contraction coupling occurs

Question 19

Twitch

Answer 19

Mechanical response to single AP

When muscle not allowed to shorten following activation, the mechanical response is called isometric twitch

Question 20

3 different types of muscle fibers

Answer 20

Type I (slow, red): contract and relax slowly (200-500ms), shorten slowly, rely on oxidative phosphorylation to produce ATP, have smaller diameter and are dark red bc have lots of myoglobin

Type IIA (fast, red): contract and relax more rapidly (40-120ms), shorten 2-3x faster than type I fibers, are more glycolytic, do oxidative phosphorylation, red (lots of myoglobin)

Type IIB (fast, white): contract and relax more rapidly than type IIA fibers, develop more isometric force, contain fewer mitochondria so only limited oxidative phosphorylation, little myoglobin

Question 21

What are different muscle fibers used for?

Answer 21

Type I used for endurance and very fine movements

Type IIA used for endurance

Type IIB used for fast powerful contractions

Different fiber types have different isoforms of contractile proteins

Muscle fibers are very plastic: if you do endurance training, you’ll increase cross sectional area of Type I and IIA fibers and decrease CSA of Type IIB fibers

Question 22

Is there a refractory period for stimulating another action potential?

Answer 22

Yes but it is a small fraction of the twitch duration so muscle can be stimulated a number of times during the twitch

Question 23

Fused and unfused tatanus

Answer 23

Unfused tetanus: repetitive stimulation at increasing rates causes oscillatory state called unfused tetanus

Fused tetanus: muscle stimulated so many times in a row that you get smoothly rising fused tetanus

Question 24

Is stimulus frequency needed to produce fused tetanus the same in type I and type II fibers?

Answer 24

No, require greater stimulus frequency to produce fused tetanus in Type II fibers than Type I fibers because Type II fibers have higher rate of cross-bridge cycling and Ca2+ pumping

Question 25

How do we physiologically regulate the force exerted by the muscle?

Answer 25

1) **Frequency** of stimulation 2) **Number** of motor units firing (ex: Type I fibers small and enervate small numbers of muscle cells whereas Type IIB fibers are largest and innervate large numbers of muscle cells)

Question 26

Concentric (isotonic) contraction

Answer 26

Muscle **shortens** as it contracts Once muscle starts to shorten, force needed to keep it shortening **decreases** then **levels off** ATP is hydrolyzed, walking up stairs harder than walking down...

Question 27

Eccentric (forced lengthening) contraction

Answer 27

Muscle **lengthens** as it contracts (oxymoronically!) Force **rises** rapidly as muscle is lengthened, to twice that produced by isometric contraction However, **rate** **of energy consumption** during eccentric contraction is very small because muscle **hydrolyzes very little ATP** (work done on muscle produces force in cross bridge and reverses power stroke and detaches actomyosin attachment before Pi and ADP released) (think of it as a mechanical force breaking cross bridge so no ATP has to be hydrolyzed--cheating!) This is why walking down stairs much less tiring than walking up stairs (reduced rate of enegy expenditure)

Question 28

Delayed onset muscle soreness (DOMS)

Answer 28

Most frequently occurs in "**weekend athlete**" or people who only infrequently exercise and then perform strenuous exercise **8-24 hours after exercise**, muscles sore and limb motion limited by **soreness**; Soreness peaks **1-3 days** after exercise and subsides over 7-10 days Can be attenuated by subsequent bouts of same type of exercise starting with modest intensity DOMS is result of **eccentric** contractions (running down hill, limb extensions against load) causing muscle fiber tearing or **damage** to **Type II** fibers (which then causes activation of type IV pain fibers due to inflammation/muscle damage) (concentric contractions produce less than half muscle damage as in eccentric contractions)

Question 29

Compare/contrast SKM and CM

Answer 29

**Satellite cells**: SKM has them and can regenerate, CM does not **Costameres**: SKM has them, CM does not Getting Ca2+ out of SR: **SKM uses EC coupling** and CM uses Ca2+-induced Ca2+ release DHP and RyR: both have them