2. Muscular System Functions
• Body movement (Locomotion)
• Maintenance of posture
• Respiration
– Diaphragm and intercostal contractions
• Communication (Verbal and Facial)
• Constriction of organs and vessels
– Peristalsis of intestinal tract
– Vasoconstriction of b.v. and other structures (pupils)
• Heart beat
• Production of body heat (Thermogenesis)
3. Properties of Muscle
• Excitability: capacity of muscle to respond
to a stimulus
• Contractility: ability of a muscle to shorten
and generate pulling force
• Extensibility: muscle can be stretched back
to its original length
• Elasticity: ability of muscle to recoil to
original resting length after stretched
4. Types of Muscle
• Skeletal
– Attached to bones
– Makes up 40% of body weight
– Responsible for locomotion, facial expressions, posture, respiratory movements,
other types of body movement
– Voluntary in action; controlled by somatic motor neurons
• Smooth
– In the walls of hollow organs, blood vessels, eye, glands, uterus, skin
– Some functions: propel urine, mix food in digestive tract, dilating/constricting
pupils, regulating blood flow,
– In some locations, autorhythmic
– Controlled involuntarily by endocrine and autonomic nervous systems
• Cardiac
– Heart: major source of movement of blood
– Autorhythmic
– Controlled involuntarily by endocrine and autonomic nervous systems
5. Connective Tissue Sheaths
• Connective Tissue of a Muscle
– Epimysium. Dense regular c.t. surrounding entire muscle
• Separates muscle from surrounding tissues and organs
• Connected to the deep fascia
– Perimysium. Collagen and elastic fibers surrounding a group of
muscle fibers called a fascicle
• Contains b.v and nerves
– Endomysium. Loose connective tissue that surrounds individual
muscle fibers
• Also contains b.v., nerves, and satellite cells (embryonic stem cells
function in repair of muscle tissue
• Collagen fibers of all 3 layers come together at each end
of muscle to form a tendon or aponeurosis.
6. Nerve and Blood Vessel Supply
• Motor neurons
– stimulate muscle fibers to contract
– Neuron axons branch so that each muscle fiber (muscle cell) is
innervated
– Form a neuromuscular junction (= myoneural junction)
• Capillary beds surround muscle fibers
– Muscles require large amts of energy
– Extensive vascular network delivers necessary oxygen
and nutrients and carries away metabolic waste
produced by muscle fibers
8. Skeletal Muscle
• Long cylindrical cells
• Many nuclei per cell
• Striated
• Voluntary
• Rapid contractions
9. Basic Features of a Skeletal Muscle
• Muscle attachments
– Most skeletal muscles
run from one bone to
another
– One bone will move –
other bone remains fixed
• Origin – less movable
attach- ment
• Insertion – more
movable attach- ment
10. Basic Features of a Skeletal
Muscle
• Muscle attachments (continued)
– Muscles attach to origins and insertions by
connective tissue
• Fleshy attachments – connective tissue fibers are
short
• Indirect attachments – connective tissue forms a
tendon or aponeurosis
– Bone markings present where tendons meet
bones
• Tubercles, trochanters, and crests
11. Skeletal Muscle Structure
• Composed of muscle cells (fibers),
connective tissue, blood vessels, nerves
• Fibers are long, cylindrical, and
multinucleated
• Tend to be smaller diameter in small
muscles and larger in large muscles. 1
mm- 4 cm in length
• Develop from myoblasts; numbers
remain constant
• Striated appearance
• Nuclei are peripherally located
15. Muscle Fiber Anatomy
• Sarcolemma - cell membrane
– Surrounds the sarcoplasm (cytoplasm of fiber)
• Contains many of the same organelles seen in other cells
• An abundance of the oxygen-binding protein myoglobin
– Punctuated by openings called the transverse tubules (T-tubules)
• Narrow tubes that extend into the sarcoplasm at right angles to the
surface
• Filled with extracellular fluid
• Myofibrils -cylindrical structures within muscle fiber
– Are bundles of protein filaments (=myofilaments)
• Two types of myofilaments
– Actin filaments (thin filaments)
– Myosin filaments (thick filaments)
– At each end of the fiber, myofibrils are anchored to the inner surface of
the sarcolemma
– When myofibril shortens, muscle shortens (contracts)
16. Sarcoplasmic Reticulum (SR)
• SR is an elaborate, smooth endoplasmic reticulum
– runs longitudinally and surrounds each myofibril
– Form chambers called terminal cisternae on either side
of the T-tubules
• A single T-tubule and the 2 terminal cisternae form
a triad
• SR stores Ca++
when muscle not contracting
– When stimulated, calcium released into sarcoplasm
– SR membrane has Ca++
pumps that function to pump Ca+
+
out of the sarcoplasm back into the SR after contraction
19. Sarcomeres: Z
Disk to Z Disk
• Sarcomere - repeating functional units of a
myofibril
– About 10,000 sarcomeres per myofibril,
end to end
– Each is about 2 µm long
• Differences in size, density, and distribution
of thick and thin filaments gives the muscle
fiber a banded or striated appearance.
– A bands: a dark band; full length of thick
(myosin) filament
– M line - protein to which myosins attach
– H zone - thick but NO thin filaments
– I bands: a light band; from Z disks to ends of
thick filaments
• Thin but NO thick filaments
• Extends from A band of one sarcomere to A
band of the next sarcomere
– Z disk: filamentous network of protein. Serves
as attachment for actin myofilaments
– Titin filaments: elastic chains of amino acids;
keep thick and thin filaments in proper
alignment
21. Myosin (Thick)
Myofilament
• Many elongated myosin molecules shaped
like golf clubs.
• Single filament contains roughly 300
myosin molecules
• Molecule consists of two heavy myosin
molecules wound together to form a rod
portion lying parallel to the myosin
myofilament and two heads that extend
laterally.
• Myosin heads
1. Can bind to active sites on the actin
molecules to form cross-bridges.
(Actin binding site)
2. Attached to the rod portion by a hinge
region that can bend and straighten
during contraction.
3. Have ATPase activity: activity that
breaks down adenosine triphosphate
(ATP), releasing energy. Part of the
energy is used to bend the hinge
region of the myosin molecule during
contraction
22. Actin (Thin)
Myofilaments
• Thin Filament: composed of 3 major
proteins
1. F (fibrous) actin
2. Tropomyosin
3. Troponin
• Two strands of fibrous (F) actin form a
double helix extending the length of the
myofilament; attached at either end at
sarcomere.
– Composed of G actin monomers
each of which has a myosin-binding
site (see yellow dot)
– Actin site can bind myosin during
muscle contraction.
• Tropomyosin: an elongated protein
winds along the groove of the F actin
double helix.
• Troponin is composed of three subunits:
– Tn-A : binds to actin
– Tn-T :binds to tropomyosin,
– Tn-C :binds to calcium ions.
23. Now, putting it all together to perform the function
of muscle: Contraction
40. Sliding Filament Model of
Contraction
• Thin filaments slide past the thick ones so
that the actin and myosin filaments overlap
to a greater degree
• In the relaxed state, thin and thick filaments
overlap only slightly
• Upon stimulation, myosin heads bind to
actin and sliding begins
41. The lever movement drives displacement of the actin filament relative to the myosin
head (~5 nm), and by deforming internal elastic structures, produces force (~5 pN).
Thick and thin filaments interdigitate and “slide” relative to each other.
How striated muscle works: The Sliding Filament Model
43. Neuromuscular Junction
• Region where the motor neuron stimulates the muscle fiber
• The neuromuscular junction is formed by :
1. End of motor neuron axon (axon terminal)
• Terminals have small membranous sacs (synaptic vesicles) that
contain the neurotransmitter acetylcholine (ACh)
2. The motor end plate of a muscle
• A specific part of the sarcolemma that contains ACh receptors
• Though exceedingly close, axonal ends and muscle fibers
are always separated by a space called the synaptic cleft
45. Motor Unit: The Nerve-Muscle
Functional Unit
• A motor unit is a motor neuron and all the
muscle fibers it supplies
• The number of muscle fibers per motor unit can
vary from a few (4-6) to hundreds (1200-1500)
• Muscles that control fine movements (fingers,
eyes) have small motor units
• Large weight-bearing muscles (thighs, hips) have
large motor units
46. Motor Unit: The Nerve-Muscle
Functional Unit
• Muscle fibers from a motor unit are spread
throughout the muscle
– Not confined to one fascicle
• Therefore, contraction of a single motor unit causes
weak contraction of the entire muscle
• Stronger and stronger contractions of a muscle
require more and more motor units being stimulated
(recruited)
51. Muscle Contraction Summary
• Nerve impulse reaches myoneural junction
• Acetylcholine is released from motor
neuron
• Ach binds with receptors in the muscle
membrane to allow sodium to enter
• Sodium influx will generate an action
potential in the sarcolemma
52. Muscle Contraction (Cont’d)
• Action potential travels down T tubule
• Sarcoplamic reticulum releases calcium
• Calcium binds with troponin to move the
troponin, tropomyosin complex
• Binding sites in the actin filament are
exposed
53. Muscle Contraction (cont’d)
• Myosin head attach to binding sites and
create a power stroke
• ATP detaches myosin heads and energizes
them for another contaction
• When action potentials cease the muscle
stop contracting
55. Myosin is a hexamer:
2 myosin heavy chains
4 myosin light chains
C terminus
2nm
Coiled coil of two α helices
Myosin is a Molecular Motor
Myosin S1 fragment
crystal structure
Ruegg et al., (2002)
News Physiol Sci 17:213-218.
NH2-terminal catalytic
(motor) domain
neck region/lever arm
Nucleotide
binding site
Myosin head: retains all of the motor functions of myosin,
i.e. the ability to produce movement and force.
56. Chemomechanical coupling – conversion of chemical energy
(ATP about 7 kcal x mole-1
) into force/movement.
• ATP is unstable thermodynamically
• Two most energetically favorable steps:
1. ATP binding to myosin
2. Phosphate release from myosin
• Rate of cycling determined by M·ATPase activity and external load
Adapted from Goldman & Brenner (1987) Ann Rev Physiol 49:629-636.
57. Shortening Velocity Vependent on ATPase Activity
Different myosin heavy chains (MHCs) have different ATPase activities.
There are at least 7 separate skeletal muscle MHC genes…arranged in series
on chromosome 17.
Two cardiac MHC genes located in tandem on chromosome 14.
The slow β cardiac MHC is the predominant gene expressed in slow fibers
of mammals.
Goldspink (1999) J Anat 194:323-334.
58. Peak power obtained at intermediate loads and intermediate
velocities.
Power Output: The Most Physiologically Relevant
Marker of Performance
Power = work / time
= force x distance / time
= force x velocity
Figure from Berne and Levy, Physiology
Mosby—Year Book, Inc., 1993.
59. • shortening
• isometric
• lengthening
(Isotonic: shortening against fixed
load, speed dependent on
M·ATPase activity and load)
Three Potential Actions During Muscle Contraction:
Most likely to cause
muscle injury
Biceps muscle shortens
during contraction
Biceps muscle lengthens
during contraction
60. Motor Unit Ratios
• Back muscles
– 1:100
• Finger muscles
– 1:10
• Eye muscles
– 1:1
61. Recall The Motor Unit:
motor neuron and the muscle fibers it innervates
Spinal
cord • The smallest amount of
muscle that can be activated
voluntarily.
• Gradation of force in skeletal
muscle is coordinated largely
by the nervous system.
• Recruitment of motor units
is the most important means
of controlling muscle tension.
To increase force:
1. Recruit more M.U.s
2. Increase freq.
(force –frequency)
• Since all fibers in the motor
unit contract simultaneously,
pressures for gene expression
(e.g. frequency of stimulation,
load) are identical in all fibers
of a motor unit.
62. Physiological profiles of motor units:
all fibers in a motor unit are of the same fiber type
Slow motor units contain slow fibers:
• Myosin with long cycle time and therefore uses
ATP at a slow rate.
• Many mitochondria, so large capacity to
replenish ATP.
• Economical maintenance of force during
isometric contractions and efficient performance
of repetitive slow isotonic contractions.
Fast motor units contain fast fibers:
• Myosin with rapid cycling rates.
• For higher power or when isometric force
produced by slow motor units is insufficient.
• Type 2A fibers are fast and adapted for
producing sustained power.
• Type 2X fibers are faster, but non-oxidative
and fatigue rapidly.
• 2X/2D not 2B.
Modified from Burke and Tsairis, Ann NY Acad Sci 228:145-159, 1974.
63. Increased use: strength training
Early gains in strength appear to be predominantly due to neural
factors…optimizing recruitment patterns.
Long term gains almost solely the result of hypertrophy i.e.
increased size.
64. Rommel et al. (2001) Nature Cell Biology 3, 1009.
The PI(3)K/Akt(PKB)/mTOR pathway is a
crucial regulator of skeletal muscle
hypertrophy/atrophy.
• Application of IGF-I to C2C12
myotube cultures induced both
increased width and phosphor-
ylation of downstream targets of
Akt (p70S6 kinase, p70S6K;
PHAS-1/4E-BP1; GSK3) but did
NOT activate the calcineurin
pathway.
• Treatment with rapamycin
almost completely prevented
increase in width of C2C12
myotubes.
• Treatment with cyclosporin or
FK506 does not prevent myotube
growth in vitro or compensatory
hypertrophy in vivo
• Recovery of muscle weight
after following reloading is
blocked by rapamycin but not
cyclosporin.
65. Performance Declines with Aging
--despite maintenance of physical activity
Performance Declines with Aging
--despite maintenance of physical activity
Age (years)
10 20 30 40 50 60
Performance(%ofpeak)
0
20
40
60
80
100
Shotput/Discus
Marathon
Basketball (rebounds/game)
D.H. Moore (1975) Nature 253:264-265.
NBA Register, 1992-1993 Edition
66. Number of motor units declines during aging
- extensor digitorum brevis muscle of humans
Campbell et al., (1973) J Neurol Neurosurg Psych 36:74-182.
AGE-ASSOCIATED
ATROPHY DUE TO BOTH…
Individual fiber atrophy
(which may be at least
partially preventable and
reversible through exercise).
Loss of fibers
(which as yet appears
irreversible).
68. Mean Motor Unit Forces:
• FF motor units get smaller in old age and decrease in number
• S motor units get bigger with no change in number
• Decreased rate of force generation and POWER!!
FF FI FR S
MaximumIsometricForce(mN)
0
25
50
75
100
125
150
175
200
225
Adult
Old
Motor Unit Classification Kadhiresan et al., (1996)
J Physiol 493:543-552.
69. • Muscles in old animals are more susceptible to contraction-
induced injury than those in young or adult animals.
Muscle injury may play a role in the development of
atrophy with aging.
• Muscles in old animals show delayed and impaired recovery
following contraction-induced injury.
• Following severe injury, muscles in old animals display
prolonged, possibly irreversible, structural and functional
deficits.
70. Disorders of Muscle Tissue
• Muscle tissues experience few disorders
– Heart muscle is the exception
– Skeletal muscle – remarkably resistant to
infection
– Smooth muscle – problems stem from external
irritants
71. Disorders of Muscle Tissue
• Muscular dystrophy – a group of inherited
muscle destroying disease
– Affected muscles enlarge with fat and
connective tissue
– Muscles degenerate
• Types of muscular dystrophy
– Duchenne muscular dystrophy
– Myotonic dystrophy
72. Disorders of Muscle Tissue
• Myofascial pain syndrome – pain is caused
by tightened bands of muscle fibers
• Fibromyalgia – a mysterious chronic-pain
syndrome
– Affects mostly women
– Symptoms – fatigue, sleep abnormalities,
severe musculoskeletal pain, and headache
73. • Proteins localized in the nucleus, cytosol, cytoskeleton, sarcolemma, and ECM.
Cohn and Campbell (2000) Muscle Nerve 23:1459-1471.
• Since the discovery of dystrophin, numerous genetic disease loci have been linked to protein
products and to cellular phenotypes, generating models for studying the pathogenesis of the
dystrophies.
Muscular Dystrophy:
A frequently fatal disease of muscle deterioration
• Muscular dystrophies have in the past been classified based on subjective and sometimes
subtle differences in clinical presentation, such as age of onset, involvement of particular
muscles, rate of progression of pathology, mode of inheritance.
74. (Some components of
the dystrophin glycoprotein
complex are relatively
recent discoveries, so one
cannot assume that all
players are yet known.)
DGC
dystrophin
dystroglycan (α and β)
sarcoglycans (α, β, γ, δ)
syntrophins (α, β1)
dystrobrevins (α, β)
sarcospan
aminin-α2 (merosin)
Cohn and Campbell (2000) Muscle Nerve 23:1459-1471.
Dystrophin function:
transmission of force to extracellular matrix
96. Developmental Aspects:
Regeneration
• Cardiac and skeletal muscle become amitotic, but can
lengthen and thicken
• Myoblast-like satellite cells show very limited
regenerative ability
• Cardiac cells lack satellite cells
• Smooth muscle has good regenerative ability
• There is a biological basis for greater strength in men than
in women
• Women’s skeletal muscle makes up 36% of their body
mass
• Men’s skeletal muscle makes up 42% of their body mass
97. Developmental Aspects:
Male and Female
• These differences are due primarily to the
male sex hormone testosterone
• With more muscle mass, men are generally
stronger than women
• Body strength per unit muscle mass,
however, is the same in both sexes
98. Developmental Aspects: Age
Related
• With age, connective tissue increases and muscle
fibers decrease
• Muscles become stringier and more sinewy
• By age 80, 50% of muscle mass is lost
(sarcopenia)
• Decreased density of capillaries in muscle
• Reduced stamina
• Increased recovery time
• Regular exercise reverses sarcopenia
Notas do Editor
Skeletal muscle attaches to our skeleton. *The muscle cells a long and cylindrical. *Each muscle cell has many nuclei. *Skeletal muscle tissue is striated. It has tiny bands that run across the muscle cells. *Skeletal muscle is voluntary. We can move them when we want to. *Skeletal muscle is capable of rapid contractions. It is the most rapid of the muscle types.
In this unit we will primarily study skeletal muscle. Each muscle cell is called a muscle fiber. Within each muscle fiber are many myofibrils.
Dark and light bands can be seen in the muscle fiber and also in the smaller myofibrils. An enlargement of the myofibril reveals that they are made of smaller filaments or myofilaments. *There is a thick filament called myosin and *a thin filament called actin. Note the I band, A band H zone or band and Z disc or line. These will be discussed shortly.
A small section of a myofibril is illustrated here. Note the thick myosin filaments are arranged between overlapping actin filaments. *The two Z lines mark the boundary of a sarcomere. The sarcomere is the functional unit of a muscle cell .We will examine how sarcomeres function to help us better understand how muscles work.
A myosin molecule is elongated with an enlarged head at the end.
Many myosin molecules form the thick myosin filament. It has many heads projecting away from the main molecule.
The thinner actin filament is composed of three parts: actin, tropomyosin and troponin.
Here is a sarcomere illustrating the thin actin and thick myosin filaments. The area of the sarcomere has only myosin is called the H band.
Here is another diagram of a sarcomere. Note the A band. It is formed by both myosin and actin filaments. The part of the sarcomere with only actin filaments is called the I band. This is a sarcomere that is relaxed.
This sarcomere is partially contracted. Notice than the I bands are getting shorter.
The sarcomere is completely contracted in this slide. The I and H bands have almost disappeared.
Which filament has moved as the sarcomere contracted? Note the thick myosin filaments have not changed, but the thin actin filaments have moved closer together.
The actin filaments are moved by the heads of the myosin filaments. In step one the myosin head attaches to an actin filament to create a cross bridge. Step two shows that the attached myosin head bends to move the actin filament. The myosin head as expended energy to create this movement. This is a power stroke or working stroke. Step three shows that energy in the form of ATP will unhook the myosin head. In step 4 the myosin head is cocked and ready to attach to an actin filament to start another power stroke.
The string of green circles represents an actin filament. There are binding sites in the filament for the attachment of myosin heads. *In a relaxed muscle the binding sites are covered by tropomyosin. The tropomyosin has molecules of troponin attached to it. *Calcium, shown in yellow, will attach to troponin. *Calcium will change the position of the troponin, tropomyosin complex. *The troponin, tropomyosin complex has now moved so that the binding sites are longer covered by the troponin, tropomyosin complex.
The binding sites are now exposed and myosin heads are able to attach to form cross bridges.*
This diagram shows the microanatomy of skeletal muscle tissue again. *The blue sarcoplasmic reticulum is actually the endoplasmic reticulum. It stores calcium. *The mitochondria are illustrated in orange. They generate ATP, which provides the energy for muscle contractions.
The next few slides will summarize the events of a muscle contraction.
The nerve impulse reaches the neuromuscular junction (myoneural junction).
A motor unit is all the muscle cells controlled by one nerve cell. This diagram represents two motor units. Motor unit one illustrates two muscle cells controlled by one nerve cell. When the nerve sends a message it will cause both muscle cells to contract. Motor unit two has three muscle cells innervated by one nerve cell.
Acetylcholine is released from the motor neuron.
Acetylcholine binds with receptors in the muscle membrane to allow sodium ions to enter the muscle.
The influx of sodium will create an action potential in the sarcolemma. Note: This is the same mechanism for generating action potentials for the nerve impulse. The action potential travels down a T tubule. As the action potential passes through the sarcoplamic reticulum it stimulates the release of calcium ions. Calcium binds with troponin to move tropomyosin and expose the binding sites. Myosin heads attach to the binding sites of the actin filament and create a power stroke. ATP detaches the myosin heads and energizes them for another contraction. The process will continue until the action potentials cease. Without action potentials the calcium ions will return to the sarcoplasmic reticulum.
Catalytic domain responsible for binding & hydrolysis of ATP, and binding actin.
Neck region responsible for transport of the load.
Converter responsible for energy transduction.
Motor units come indifferent sizes. *The ratio is about one nerve cell to 100 muscle cells in the back. *Finger muscles have a much smaller ratio of 1:10. *Eye muscles have a 1:1 ratio because of the precise control needed in vision.
By way of introduction, I’ll briefly reiterate some points that John made in the previous talk…
Increased susceptibility
Decreased ability to recover and prolonged deficits
Because muscles are injured repeatedly throughout life, these two observations, along with others provide circumstantial evidence that muscle injury plays a role in the development of atrophy and weakness with aging.
Muscles of animals of all ages, except perhaps the oldest-old, can continue to adapt to the habitual level of activity.
ATP or adenosine triphosphate is the form of energy that muscles and all cells of the body use. *The chemical bond between the last two phosphates has just the right amount of energy to unhook myosin heads and energize them for another contraction. Pulling of the end phosphate from ATP will release the energy. ADP and a single phosphate will be left over. New ATP can be regenerated by reconnecting the phosphate with the ADP with energy from our food.
Creatine is a molecule capable of storing ATP energy. It can combine with ATP to produce creatine phosphate and ADP. The third phosphate and the energy from ATP attaches to creatine to form creatine phosphate.
Creatine phosphate is an important chemical to muscles. *It is a molecule that is able to store ATP energy. *Creatine phosphate can combine with an ADP * to produce creatine and ATP. This process occurs faster than the synthesis of ATP from food.
Muscle fatigue is often due to a lack of oxygen that causes ATP deficit. Lactic acid builds up from anaerobic respiration in the absence of oxygen. Lactic acid fatigues the muscle.
Muscle atrophy is a weakening and shrinking of a muscle. It can be caused by immobilization or loss of neural stimulation.
Hypertrophy is the enlargement of a muscle. Hypertrophied muscles have more capillaries and more mitochondria to help them generate more energy. Strenuous exercise and steroid hormones can induce muscle hypertrophy. Since men produce more steroid hormones than women, they usually have more hypertrophied muscles.
Steroid hormones such as testosterone stimulate muscle growth and hypertrophy.
Muscle tonus or muscle tone refers to the tightness of a muscle. In a muscle some fibers are always contracted to add tension or tone to the muscle.
Tetany is a sustained contraction of a muscle. It results from a rapid succession of nerve impulses delivered to the muscle.
This slide illustrates how a muscle can go into a sustained contraction by rapid neural stimulation. In number four the muscle is in a complete sustained contraction or tetanus.
The refractory period is a brief time in which muscle cells will not respond to stimulus.
The area to the left of the red line is the refractory period for the muscle contraction. If the muscle is stimulated at any time to the left of the line, it will not respond. However, stimulating the muscle to the right of the red line will produce a second contraction on top of the first contraction. Repeated stimulations can result in tetany.
Cardiac muscle tissue has a longer refractory period than skeletal muscle. This prevents the heart from going into tetany.
Isometric contractions produce no movement. They are used in standing, sitting and maintaining our posture. For example, when you are standing muscles in your back and abdomen pull against each other to keep you upright. They do not produce movement, but enable you to stand.
Isotonic contractions are the types that produce movement. Isotonic contractions are used in walking and moving any part of the body.