1
Q
Is muscle homogenous tissue
A
no it is heterogenous
-what does that mean?
this means that muscle tissue is not just uniformly made of one cell
-it is made of multiple types of cells and components
-means that we cant treat it the same from person to person as the components are different for each individual
so same parts but patterns and composition are different
2
Q
how many proteins are in a muscle fibre
A
20 - 30 thousand
3
Q
are muscles highly adaptable
A
yes, it is known as muscle plasticity (can change its structure and size based on external forces), can change it based on how we use it
-protein expression in muscle will determine what it looks like and how it function
4
Q
What are the systems that is within a musle cell
A
A) Contractile System (Myofibrils)
-Contractile proteins (Actin and Myosin)
-Regulatory proteins (troponin and tropomyosin)
Remember: myofibrils are just composed of a bunch of sarcomeres which are composed of actin and myosin
sacromeres: repeating contractile units
job is to create force
Actin: provides binding site for myosin
Myopsin: motor proten that forms cross bridges and generate power strokes using atp
B) Ca Regulation System
-coordinates contraction by controlling Ca availability
-signals proteins to work
-Sarcoplasmic reticulum (SR), an this stores ca and releases it during depolarization with release of ca into sarcoplasm , uptake occurs when ca is pumped back into sr using ca atpase pumps
C) Excitation System: Electrical potential
-gets signal into muscle cell from brain
-muscle tissue is excitable tissue, means that electrical charge changes by moving ions to change excitability
-Sarcolemma (conducts action potential)
-T tubules (carry the action potential deep into fiber because they are invaginations in muscle fibers, ensures myofrible is activated at once)
THIS ALLOWS CONTRACTION BECASUE action potnetial travells down t tubules and sarcolemma and this triggers release from SR (CA release)
D) Metabolic energy system:
-ATP broken down to adp and Pi (ATP hydrolysis)
-muscles need this constant supply of ATP to work or else it will fatigue
-Need ATP FOR:
1)Myosin head cycling (cross bridge power stroke)
-CA pupmping back into SR (relaxation of muscle)
-Sodium potassium pump to restore membrane potential after action potential)
-need atp to contract and produce force
E)Nucleus (Multinucleated system)
-many nuclei on periphery of cell
-allows for regeneration potential (via satellite cells)
-allows it to adapt (regulates gene expression for hypertrophy, atrophy, metabolic shifts)
-allows for response to stimuli
5
Q
What is the on and off switch for contractions
A
calcium
6
Q
big picture of 5 systems
A
Big Picture: Integration of All 5 Systems
Excitation (C): AP → depolarization.
Ca²⁺ Regulation (B): SR releases Ca²⁺.
Contraction (A): Cross-bridge cycling → force.
Metabolism (D): ATP fuels contraction, ion pumping, and relaxation.
Nucleus (E): Oversees adaptation, regeneration, and long-term function.
7
Q
What does the muscle anatomy look like
A
tendon-> connective tissue -> muscle fascicle (bundle of muscle fibers) -> muscle fiber -> nuclei
so many nuclei
muscle fiber : so many cells make it
-many proteins
-
8
Q
Components of a muscle fiber
A
Muscle Fiber:
-long cylindrical cell
-made of many myofibrils
-surrouned by sarcolemma
Myofibril:
-many sarcromeres in series
-surrounded by sarcoplasmic reticulum
-SR stores ca and releases in response to action potentia, allowing sarcromers to contract
Sarcomere:
-smallest funxtional contractile unit
-composed of actin and myosin that form thick and thin filaments , the thick and thin filaments are arranged in a repeating pattern that form the sarcomere
-these are bound by Z discs
Thick filaments: made of myosin
Thin filaments: actin, tropomyosin and troponin
9
Q
What allows everything to stretch myofibril
A
the contractile proteins which make up the sarcromere
10
Q
Shortening leads to what
A
shortening of myofibrils (sarcometres) leads to contractile force
11
Q
What is the relationship between sarcoplasmic reticulum and myofibril
A
-SR allows for release uptake of ca, ca is stored here
-muscle uses calcium for contraction, it allows shortening to initiate
-when calcium is released, the myofibril gets filled with the calcium, which allows for contraction
12
Q
What is the purpose of the T tubule
A
it is extension of the sarcolemma, it allows for action potential to travel deep into the myofibril
allows muscle to contract properly
REMEMBER: what happens at sarcolemma- depolarization and other signals from other cells, ie hormones, cytokines, things are being released around this membrane, if cell was small, then we dont need t tubules to activate cell, and send signals to cell but since this cell is huge we need these t tubtules to be able to send signals to the muscle deep in it to contract proeroly
-allows action potential to migrate deep into muscle adn this will activate the myofibrils deep in muscle so this allows for more forceful contraction
13
Q
Say: i have a myofiber and it has 10,000 myofibrils, but i only activate the 100 that are near the sarcolemma, what kind of force would be produced
A
weak force
the more myofibrils I activate, the more forceful my contracrtions will be
14
Q
The more myofibrils I activate, the more ________ my contractions will be
A
forceful
15
Q
How can i get the most forceful contravction
A
by actiating all my myofibrils by sending the signals deep into the muscle to penetrate all the myofibril within the muscle fiber cell
16
Q
REcap of what happens in contraction
A
1) Send AP across sarcolemma down into t tubules
2) this causes SR to release CA and this calcium binds to specific proteins within sarcomere and allow crossbridge formation (interactions in the sarcomere and then the muscle shortens)
17
Q
Do we have alot of mitochondria in muscle
A
yea because we need lots of ATP so the muscle is HIGHLY OXIDATIVE compared to other tissues in body, if mito doesnt provide, then muscle doesnt contract properly
18
Q
Say i am going for a long run and then at the end of it it is getting harder why?
A
because there system is not adapted to this so there is essentially not alot of atp (one of the things)
a trained athlete can run for longer because their systems have adapted an so their mitochondria can provide more atp than average individual
19
Q
if an intdividual has a mitochondrial disorder, what would this mean for muscles
A
their muscles will fatigue faster as atp is low
20
Q
What are the components of myofibril
A
made up of series of sarcomeres
-sacomeres are made of thick and thin filaments
THICK: Myosin ( motor protein that changes its conformation “Flexes”
THIN: ACTIN and regulatory proteins troponin and tropomyosin
Strucutural (cytoskeletal proteins): Titin and Nebulin
-give sarcomere some form and shape, important because if this changes, we wont get optimal contraction
21
Q
What is sarcomere
A
smallest funxtional unit of muscle fiber
22
Q
what are the imp proteins
A
contractile proteins: Actinand myosin
Regulatory proteins: troponin and tropomyosin ( help regualte the interactions between actin and myosin)
Cytoskeltal proteins: titin and nebulin
23
Q
What is the thin filament made up of
A
Actin monomers
-they are put together into two strands and twisted to form ACTIN FILAMENT
Filament:
-has myosin binding site
-on top binding site is TROPOMYOSIN and its job is to reglate the bining site by blocking or openign the binding site using TROPONIN complex
Troponin:
made of 3 subunits
-responds to calcium
-as calcium is released it binds to troponin and changes troponin conformation, which allows tropomyosin to move which EXPOSES bidning site
24
Q
If there is no calcium, what occurs in the thin filament
A
nothign
troponin will not change conformation, therefore tropomyosin will not move from blocking thr myosin binding site and therefore muosin cannot bind
25
1 molecule of troponin for every
7 actin monomers
26
What are the components of the thick filament
MYOSIN
-rod tain, two heads at end and hinge region
-a bunch of these together create thick filament
-head is the actin bidninh site
-atpase in head (Breaks down atp in the head)
-energy from atp changes myosin conformation, causes head to swivel back and forth which causes muscle to shorten
27
Where is the actin binding site on myosin
myosin head
28
sooooo
when muscle shortens:
myosin is using atp, this causes head to swivel using that energy, this causes myosin to move the thin filament since the head binds to the actin filament
this can only happen if:
1) ATP PRESENT
2) CALCIUM because this allwos the head to bind to actin
29
so muscle can only shorten "contract" if
atp present (to move the muosin head)
calcium present (To allow myosin to bind to actin (
30
what are the components of the sarcomere
-spands from one z disk to another
-Z disks hold the thin filaments together filaments together
-M line: hold thick filaments
this orientation allow sof rmaximal interaction between myosin adn actin
31
A cross section at M line will have... what about H zone? what about I band? what about Oter edge of A band
M line: thick filament plus accesory proteins
H zone: Only thick filaments
I band: thin filaments only
A band outer edge: both thicl and thin
A band inner : only Thick filaments because A band inner is H zone
32
Sliding filament theory of skeletal muscle contraction
As muscle contracts : there is more overlap of the thick and thin filaments
33
Muscle damage can cause significant loss of firce because
after eccentric exercise:
-sarcomeres are pulled apart, so structure is deteriorated, this means that there is less overlap so force produced after this is so much less
-decrease in performance or force because the structures are damaged
34
the more myosin heads interact with actin
the more force is produced
35
Definitions of some things
sarcolemma: outer memb of muscle fiber
t tubules: invaginations of sarcolemma into the fibers interior along vertical line to fiber acis
=lume of t tubule is continous with extracellular space
composition:
-phospholip bilayer and a variety of specialized proteins (Channels, pumps, transporters)
36
Sarcoplasmic reticulum
-extensive muscle membrane system aroudn EACH myofibril
-regulates intracellular free calcium
fxns:
Ca storage, release in response to muscle stimulation, removal from cytoplasm when repolarize sarcolemma
-remember when calcium is released, it goes and bidns to troponin which changes conformation and causes tropomyosin to move, when calcium is reuptaken, the muscle relaxes because this all resets
37
So what is the interaction between t tubule and sr
DHPR receptor at t tubule
RyR at SR, and SERCA
remember: high conc of ca in SR, low in cytosol
so during myscle contrac:
brain sends signal , gets to motor neuron, motor releases AcH (acetylholine), depolarizes the membrane, AP goes along sarcolemma and into t tubule, if ap releases a specific threshold (voltage), it activates DHPR,
DHPR needs a specific voltage change conformation which is good because we only want a specific voltage ro cause contraction
DHPR links this signal to RYR (in cell, aka calcoium release channel), changes ryr conformation which opens channel for calcium release, so ca can now bind to troponin
AS long as calcium is there and we have atp contraction continues! -usually only run out of the amoutn of atp needed for maximal
how do we stop contraction then? by stopping action potention, not through serca cause serca is always working, it will reduce ca but if ca keeps going out through ryr then it cant stop it.
-through SERCA (SRcaclium aTPase), for every 1 atp, 2 calcium move so it lowers calcium back into sr, lowers ca levels
38
is serca always working
yes... it can be regulated to work faster
39
muscle fiber types
-heterogenous
-different types characterized by speed of contraction (production of force), fatigue characteristics, Metabolic characteristics
Can categorize by:
A) Speed: type 2 faster than typw 1
Vmax: maximal rate of shortening
-faster fibers reach this max quicker
-rate related to myosin atpase activity (an how fast actin and myosin come together), which is dependent on Myosin heavy chain isoforms
-abosulte force does not differ but it s speed does
B): Fatigue characteristics
-how we can maintain contraction
types of cateogries:
1) fast fatigable:
2) Fast resistance
3) Slow: take long time for force to decrease
c) Metabolic characteristics:
-two major systems that provide atp for muscle are aerobic and glycolytic
-each system has its own enzymes that have activity, activity is higher for certain fibers
1) Fast Glycolytic (FG), relies on glycolysis - fast fiber is generally glycolytic but we can change these properties
2) Fast Oxidative Glygcolytic (FOG),
3) Slow Oxidative (SO), contract slowl
Succinate Dehydrogenase (Krebs cycle in mito, so determines aerobic met), when someone undergoes endurance trainign they will have lots of this so this means that they fibers are able to make atp aerobicallu, so they are more fatigue resistant but produce atp slowly, indicates when a muscle is using oxidative (aerobic met). means that they are more fatigue resistant but "slow" because takes longer to make atp but atp seen in bigger amounts, under endurance "aerobic" trainign program, see that high sdh content because we increased mitochondrial content
-now every one of fiers are good at producing atp aerobically, BUTTTT we did not change the fiber type (ie it is still type 2 but now because we changed mito activity it is now more fatigue resistan,
d)morphological characteristics
a.muscle fiber diameter (type 2 generally larger)
b. capillary density (more oxidative needs more oxygen, so higher capilarry density)
c.myoglobin content (o2 transport thing, high oxi, high this)
d. organelle content (mito density high in oxi fibers (usually type 1), high SR in type 2(bc they are better at regulating calcium concentration so they release and take it up faster so their sr is more)
White vs red muscle (red is highly oxi)
40
do humans express hciiB
no but rats do
41
mysoin heavy chain isofirms
different types of myosin, the type determines myosin atpase activity, and essentially the atpase that is there
Humans have 3:
HCIIx > HCIIa> HCI
rats also have HCiib (fastest)
42
the contraction and relaxation of type 2 fibers is
faster than type 1
tiem ti takes to get to max is longer in type 1
-means that type 2 has faster shortening velocities
SOO even if the type of force is the same, the velocities will differ for each type of fiber
43
If i have two muscles, both same size but one is only made of typ1 one is only mae of typ2 which one produces more foce
both will produce equal force! , only the rate changes because they are the same size so both muscles have the same crossbridges and myofibrils and everything else
only POWER is different: because power is force per unit time! so unit time will differ, power will be more for type 2
44
succinate dehydrogenase importance
indicates when a muscle is using oxidative (aerobic met). means that they are more fatigue resistant but "slow" because takes longer to make atp but atp seen in bigger amounts, under endurance "aerobic" trainign program, see that high sdh content because we increased mitochondrial content
-now every one of fiers are good at producing atp aerobically, BUTTTT we did not change the fiber type (ie it is still type 2 but now because we changed mito activity it is now more fatigue resistant), we can change fiber types but takes longer and harder.
45
can we change one fiber characteristic without changing the other
yes , ie met activity can be changed without changing the fiber type
makes it heterogenous
differs greatly between individuals
46
if i wanna know if a fiber is highly oxidative imeasure
mito enzymes, mito contents, ie SDH
47
if i wanna know if a fiber is hyghly glycolytic
-glycolytic content an enzymes
48
SR fxn and ifferences in fiber type
type 2 : more ca atpase, more serca 1, more ca uptake, more ca release, more ryr channels
type 1: less of everything, uses serca 2
49
look sy dlifr 25 unit 1
50
motor units
when we produce force, we do not use all muscle fibers !
-each motor unit innervates a certain amoutn fo fibers, allows us to grade force
least force produced: need 1 motor unit, cant just innervate 1 fiber
-recruitment of motor units is the most important means of controlling muscle force
type 1 motor units are recruited first, as force increases, we incerase type 2a, and then all fibers
51
how to increase force
1. recruit more motor units
2. increase frequency
-summation, increase the force we are geting even from a singular motor unit
-tetnus (max contraction for a motor unit), we can increase frequency until we get to this point
-stimualte before it is fully relaxed, allows us to superimpose it toadd the forces together to make a stronger force
52
why is type 1 recruited first when increasing force
because the type 2 fatigue faster,
type 1 recruited first because they are the most oxidative and therefore they can be used more and adapted more
53
to produce max force
ALL MUSCLE IS USED!!!!! becaues most ordinart people have only 7% type 2, so to have maximal we need to recruit type 1 type 2, everything
54
summation of force in fast and slow muscle
EDL is fast muscle: need a high frequency to get maximal force out of it (hz is frequency), less stimulation needed for slow muscle to get max force
55
Physiological profiles of motor units
Slow fibers: tend to be apart of SMALLER motor units (less fibers per unit), fast are in larger
-difference in force due to difference in # of fibers / motor unit because think about how many more fibers are contributing to the force (more fibers will give more force)
-number of fibers dictate how much force we can produce
56
All the fibers in a motor unit
have to have the same properties, because when u use it u are using all those fibers so they are all going to be adapted
-if they are two seperate motor units (even if they are type 1 fibers) they will be different between eachother, slight differences between these motor units because one might be used for standing while one for sitting
57
the ones recruited first will be more than one that is never used
more oxidative than one that is never used
so the "motor units: for a standinglong jump will be more oxidative to the motor units of standing as i do that evertyday
58
every FIBER within the same motor unit
have to have the same characteristics bcase they are being used the same
59
every motor unit within a muscle
likely ifferent to the other ones , unkess multiple motor units are recruitedat the same time (ie if 5 motor units are recruited to stand, those 5 motor units will all look the same)
60
Fiber type transformation sequence
Hybrid fiber types exist in that to change from one type to another, we are going to go through different stages
-fiber types exist in a continuum and we group them for convenience into 3 main types
i (SO
IIa (FOG)
IIb (FG) (humans dont have b so x)'
For wxMPLW: say we hacve a fiber that is made of 40% 2a 60%2x... if we stimulate it properly, the 2x myosin will slowly go way, and 2a in slowly increase (this means that MHC is changing (remember the fiber types are dependent on atpase activity which is dependent on myosin heavy chain isoforms, so if we change this protein expression in the muscle we will change the fiber types (we decrease expression of one and increase the other)
-now we stimulate it more and more until we make the desired one, we just change the protein expresssion to go from fast
- we have man different fiber types and then it just changes based on what we are
THIS ALL alows for flexibility in the rate of contraction in the muscle ; muslcle is heterogenous
61
Say you have something like " IIBD and IIDB which one is faster,
BD because there is more B than D and B is faster than D
62
The difference between type 1 and type 2 force production
greter force proucetion by the type 2 motor units than the type 1
63
6 small fibers vs 2 large fibers, which will produce more force
2 large, because more crossbridges can be formed
64
why do we recruite type 1 first
we can use them longer, fatigue less, motor units are smaller so more fine tuning, ability to slowly grade force is much better (gradually increase), want to be able to waklk then run
65
Force vs rate of force development
type 2 will have a faster rate of force development
type 2 typically also have more muscle fibers per unit so they will jave greater force production
66
3 main ATP delivery systems in muscle, provide atp for the processes in the next car
1) High Energy Phosphate Transfer: HEPT
-get the phosphate from creatine phosphate and transfer it to the adp molecule to make atp
transfer of phosphate group ro make ADP into ATP
-NO O2 nEEDED
1) STORED ATP+h20 -> ADP + Pi+ H+ + Energy
2) Phosphocreatine is used with adp to restore it
PRIBLEM WIHT THIS SYSTEM: only uses stored atp therefore it will only give around 20 seconds of work, after that the stores become depleted.
2) Glycolysis: breaks down glucose or glycogen (stored in muscle)
-does not involve o2
-large amount of ATP can be generated per unit of time, due to high activity of enzyes in this pathway
-relatively quick, large amiunt of atp can be made per unit time ue to high activity of enzymes in this pathway; MEDIUM TO HIGH POWER
-BUT cannot rely heavily on this for prolonged periods: 1) availabilty of substrates (muscle glycogen), 2) buildup of lactic acid (H+ caused acidosis)
-moderatly capacity
Energy investment phase of glycolysis:
Phosphorylase enzyme: breaks down glycogen
Hexokinase (to break down glucose); atp needed, phosphofructokinase (atp needed)
3) Oxidative Phosphorylation
-complete combustion of fats and or carbs
-requires o2 (electron acceptor), if no oxygen, limits what we can do
-happens in mitochondria,
-have an "unlimited supply", so we dont get lost in less substrate concentration, and therefore wecan ideally make alot
-however, rate of atp regeneration is low, so system has low-moderate power and is limited by o2 supply
breakdown fat using beta oxi,
things breakdown and enter kreb as acetly coa, we will make small amount of atp , ATP and NADH too, we move this to ETC and this is where oxidative phosphorylation occurs.
essentially, fatty acids turn into acetyl coa, or acetyl coa comes from pyrvuate, and it is oxidized to form FADH and NADH, which is brought to electron transport chain
-5 complexes, 4 electron trasport, 5th is for atp making, electrons donated and this causes hydrogens to pump
67
What are the 3 main ATPASES in muscles (use atp)
1) SERCA : uses atp to pump ca back into SR
2) MYosin ATPase: uses it to swivel the head to contract and grab actin and swivel, : rigor : people that died no atp so they are swiveled
3) NaK+atpase: ion gradient near sarcolemma influences action potential, if this gradient breaks down, so does action potential
we need ample and quick atp
68
if oxygen is low, what to o
slow down or stop (this allows us to still do aerobic metabolism, allows us to go for longer, now we can go for longer), allows endurance runners to go for longer)
69
why cant we rely on glycolysis for long ime
1) availability of subtrates decreases (muscle glycogen decreases)
2) buildup of lactic acid
-lactic acid is very strong acid that disscoaites into lactate ion and H+
lactic acidosis and glycogen depletion limit work intensity
WE DONT WANT TO USE TOO MUCH BLOOD GLUCOSE BECAUSE THE BRAIN RESLLY NEEDS THIS
70
enzymes of glycolysis, investment of glycolysis
Phosphorylase: breaksdown glycogen
hexokinase: breaks down glucose aTP NEEDED
Phosphofructokinase (fructose 60biphosphate to fructose 1,6 biphosphate aTP NEDED
-PYRUVATE MADE, 4 atp made, nadh is made (accepting electrons) we want to bring this to ETC so that we can make more ATP, enters krebs cycle)
-in perfect world we move all our pyruvate and nadh into etc
NADH builup causes us to donate it back to pyruate which makes LACTIC ACID
its either we have no atp or we have a buildup of lactic acid
-ifno o2 we have (if we cant accept o2, then we slow down and gradient drops so aerobic capacity declines, so aerobic system needs to be goo
71
Muscle Plasticity
-muscle adapts during develp and aging
-adapts to various diseases
-adapts to demands (level of activity)
-increase muscle use (endurance training, strength training)
Decrease muscle (immobilization, sedentary lifestyle)
72
Skeletal Muscle Development
SKELETAL MUSCLE CELLS: derived from MYOGENIC stem cells found in embryonic MESODERM,
-these migrate to appropriate sites n differentiate into MYOBLASTS
-MYOBLASTS aggregate an fuse to form multinucleated MYOTUBES
-myoTUBE attach to eachother to form a central chain of nuclei
MYOGENIC -> MYOBLASTS at site -> Myotibes
-myofibrils then lead to hypertrophy of muscle, increase in girth adn length, longer muscles are stronger because they have more sarcomere so more force
-nuclei of myotubes move to periphery
at 24 weeks, muscle fibers in each human is set
***** NO NED ADDITION OF MUSCLE FIBERS ONLY MYOFIBRILS WITHIN FIBER, we don make new fibers we just extend the length
-developing muscle fibers have several myosin forms, embryonic and fetal form, once muscle starts contraction, fetal is replaced by adult myosin incluing type 1 and typ2
-approx 100-200 nuclei per mm of muscle length
-#nuclei correlates to fiber size, more nuclei means larger fiber
-greater number of nuclei, the greater the protein production, need more protein to maintain size, changes in nuclei number affect size, some diseases do this
-muscle cells are post-mitotic; therefore cant divide
-satellite derived from non fused myoblasts that remained undifferentiated
72
LECTURE 2
73
What happens to the myoblasts that DO NOT FUSE
-they will stay as single cell with MITOTIC potential (SATELLITE CELLS found in mature muscle)
74
in humans by early weeks
most muscle groups are well defined, and we see the synthesis of contractile proteins an the first signs of cross striations
-this starts to make myofibrils
75
HOW DOES MYOBLAST TURN TO MYOTUBE
TRANSCRIPTON FACTORS!
-binds to dna so we can make mrna (bind to specific regions of dna so we make very specific products) - upregulate these muscle transcription factors
Transcriotion factors:
MYF genes (myogenic factor 5), myogenic determination (MYOD), and myogenin
-if these are overexpressse in non myogenic cells, these cells will form muscle
WHhat bloclks these transcription factors? -MYOSTATIN and ID (inhibitor of differentiation), inhibit myod
76
What blocks the myf (transcription factors), myod and myogenin
ID (inhibitor of differentiation and MYOSTATIN
77
myoD / myf5 Defiency vs Myostatin Deficiency
Myod/myf-5 deficiency
-lack of these genes means no skeletal muscle development
-lack of myoblast proliferation and differentiation
Myostatin Deficiency: increased muscle and decreased adiposity
-myostatin is a growth factor, inhiits muscle proliferation and differentiate so if we dont have it the muscle just keeps growing
78
why do we want nuclei at periphery
if dense nuclei in middle, sarcomere have to go around them
-also: signals need to make their way deep into muscle , signals would have to travel so far to signal things about transcription
79
would it be easy to replicate a muscle cell
NO because it is a long fiber with many contractile proteins so that is vety hard to replicate which is why it is in a post mitotic state, innervation at each fiber, so this makes it hard, lots of connective tissues, would need more motor neurons
80
Satellite cells
undiferentiated myoblasts
-lie between plasma and basement membrane, it has its own plasma mem too so it is independent of muscle fiber but found underneatht he basal lamina
-provide genetic material to existing fibers, satellite cells can replicate and donate dna when needed
-provie genetic material that is needed for muscle growth, repair and hypertrophy
-they can be active an divide or fuse
81
Neuromuscular junction formation during muscle development
-at 10-11 weeks at gestation, motor neurons innervate the fiber
NOTE- acetylchloine receptors before innervation are all over the cell, when the nerve makes contact however, receptors for acetylcholine begin to aggregate to the neuromuscular junction
-as muscle ages, extrajunctional ach receptors decrease bwhile juntional receptors increase
82
number of fibers doest increase but
cross sectional area does, each fiber increaess nearly 10 fold from newborn to adult, HYPERTROPHY not hyperplasia, because existing fibers get larger
however max cross senctional area is reached shortly after puberty, but this is affected by training
mean fiber csa is 3500-7500 um3 in males, and 2000-5000 in female
83
Skeletal muscle strngth characteristics
-increase in strength during puberty
-larger muscles are generally stronger, usualy this is what is measured if there is a development issue, but the more u do it, the stronger u get at it, so not a great measure of disease
-increase in strength onset puberty (testosterone si builds muscle better in male (anabolic steroids)
84
skeletal muscle strneth in boys and girls
-boys have increase due to testosterone
BEFORE PUBERTY: muscles of lower limb grow in proportion to body weight because limbs bear weight of body
but during puberty: skeletal muscle grows faster than the change in body weight
85
AGING numbers
changes are slower later in life, aging is a time related processs,
25-40: little muscle wasting, less than 10%
30 is when we start to see loss in muscle, known as SARCOPENIA
40-50 years of age is when we see a downward trend change in muscle, 50% can be lost , usually 20-30% based on studies between 40-90
1-2% loss per year at age 50
86
why is it hard to differentiate between age related and disease related muscle decline
often are intertwines, alterations in muscle function are due to both often
87
what is sarcopenia
age related muscle loss greek for poerty of flesh
-starts at 30 years old
Consequences:
loss of strength, coordination, mobility, health , social and economic burden
US says 45% of 65+ have some degree of sarcopenia, costs around 18 billion a year
Estimated by 2031: 23-45 % of canadiasn are 65+,
by 2056, 1/10 canadians are 80+
88
risk of diability increases with
severity of sarcopenia
89
Muscle Atrophy in Animals
-occurs in animals
-therefore aging is. BIOLOGICALLY CONSERVED PROCESS
-environment contributes but it is noermal
muscle to body weight ration: decreases with age
90
What are the general aspects of sarcopenia?
NOT JUST MUSCLE SIZE CHANGE
1)Muscle fiber atrophy IN BOTH types (but more in type 2) -crosssectional area may not look different because increased fat adn connetive tissue but muscle decreased
-shrinkage in fiber size!
2)loss of # of muscle fibers: greater loss of type 2 as they switch to type 1
3) Slowing of contractile proteins of the muscle
--result of less type 2
-since type 2 switch to type 1, contractile proteins slow down
-loss of motor neurons that supply type 2
-excitation contraction coupling is slower for type 1 isoform of myosin
CONSEQUENCES:
-more type 1 proportionally
-decreased force
-decreased speed
-less endurance
-power decreased
-increase fatigability (even though type 1 is more, we have less overall fibers (decreased size) so less fibers more work so fatigability)
-reaction tye slower (loss type 2)
FUNCTIONAL ALTERATIONS:
-less muscle mass so less muscle strength an whole body perofrmance
-this decline occurs at faster rate in males
-aerobic capacity (how well lungs can deliver oxy and how well muscle can use), high aer usualy means tissues functionaong better. for atrophy aerobic capacity is declining
OVerall implications:
less activity , more obestiy, more insulin resistant (because too much sugars in blood stream, body cant keep up, so t2 diabetes, hyptension. cardiovascular diseases all increase
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does atrophy lead to more decrease in fatigability befcause we have more type 1 now
now because we overall lessened the muscle fiber # therefore this means that there will be less fibers to produce the same work so increased fatigability
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why is there more type 1 than 2
MHCII synthesis rate decreases with age, decreased is due to decreased production of mRNA
so myosin 2 is not as abundant because MHCII decreases with age
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so what is lost with age
-loss of muscle size, muscle fibers, contractile proteins
-loss of motor units
-decrease in MHCII production so more type 2 instead
-muscle mitochondrial proteins synthesis rate (FRS) also decreases
-ocidative enzymes activity also decreases
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LEC 3
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Muscle diseases
-not associated with aging
Myopathies: muyscular dysfunction due to changes that occur at the muscle or muscle fiber
2 types
a) Loss of Mass
-atrophic (reduced size of individual fibers, # remains constant, some fibers may lost over period of time
2 types of these:
-secondary
-inactivity
-destructive (fibers are destroyed, damaged or die, therefore number of fibers is reduced)
b)normal mass (abnormal fxn)
-channelopathies
-metabolic myopathies
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Myopathies vs Neuropathies
Myopathies: -muscle dysfunction is due to changes that occur at the mucle or muscle fiber
Neuropathies: muscle dysfunction due to changes that initially occur at the nerves innervating the muscle "signal from nerve is lost or impaired"
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Secondary (ATROPHIC MYOPATHY)
-loss of muscle mass is secondary consequence of another disease or state of metabolic stress
-aka secondary myopathies
EX of diseases that cause this are: starvation, cancer, HIV, diseases associated with raised cortisol levels, consiquence of glucocorticoid treatment. (Antiinflammatry treatment), hypothyroid disease
-type 2 fibers atrophy because THESE ARE USED TO A LESSER DEGREE IN COMPARISON TO TPE 1)
-this is because protein is needed for a fuel source for other vital organs or tissues
-fibers become small but NOT lost
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Inactivity (atrophic myopathy)
-usualy a result of injury or immobilization
-in sedentary individuals
-can be made worse by a disease that promotes sedentary life ie treatment strategy or inactivty because they are sick (best rest, cast for lim, restricted movement)
-changes to muscle size adn function
EX: caste leg shows 40% loss in thigh volume after 6 weeks, with most happening in first few weeks due to shrinkning of muscle fibers
ex 2: cross country skier had 81% type 1, went doewn to 58 after accident
-more observant in type 1 fibers, but still affects type 2 (this is becasue we are not using it, type 1 usualy is used alot for normal activity if we are not using it muscle size drastically decreases)
THE MORE U USE THE MUSCLE THE MORE IT IS SUSCEPTIBLE TO INACTIVITY INDUCED CHANGED because we are no longer using it to the potential that we usually are ( have to keep using it to have the proteins and aerobic resp remember type 1 are highly oxidative , if we do not use this then their mito and capillary networks regress faster), they need constant recruitment stimulus to stay big, succinate dehydrogenase decreases (oxidative enzyme) and glycolytic enzyme glycerol phosphate dehydrogenase increases)
-slow muscles also change to fast (in contrast to endurance activity that shows fast to slow)
-size and force production decrease
-vmax increases in "slow" muscles because MHC and MLCisoforms changes to type 2 ones
Consequences:
-loss os strength
-fatigue (due to atrophy in all fibers partically 1 and loss of slow fibers by switching)
-metabolic alterations (decreased ability to maintain aerobic resp due to less slow so this machinery is gone
-need for higher frequent stimulation to maintain force (bc more type 2 now)
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during inactivity atrophic myopathies what enzymes increase and what decrease
succinate dehydrogenase decrease
glycerol phosphate dehydrogenase increases because we LOSE more type 1 than 2
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Desctructive myopathies: Familial
known as "Muscular dystrophies"
ex: Dechenne MD (MOST SERIOUS), Becker MD, Limb girdle MD are common
-disorders that lead to fiber destruction
-continous and extensive replacement of lost fibers with new muscle, fat and connective tissue
-typically satellite cells are able to repair damage, but in musclular dystrophy, damage is so ssevere, satellite cant keept up
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Duchenne MD
-most serious
-defective gene on X chromosome that is recessive, therefore, more common in males (1;3000 live births), less in females because they hae one fxn X
-require wheelchair gy 10, death by 20
BIOPSY shows: decreased sfiber size, (some increase in size because they are making up for lost fibers) centralized nuclei, areas with no muscle because lost fibers
-also see lots of satellite and immune cells near it
-they lack Dystrophin gene/ protein, this is part o dystrophin complex ( PRotein essential for cellular integrity and structure, also needed fr signalling across sarcolemma and into extracell matrix)
-lack of these proteins lead to continous amage and repair cells
For becker disease: imcomplete dystrophin protein is made (deletion of some gene but not all)
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Dystrophin
whole complex, spans from outside to inside f cell
-important for cellular strcuture and integretiy, and hekps with cell signalling from outside ot inside
-complex made of many proteins
-anchors to sarcolemma to most superficial myofibrils, links myofibrils and this helps distribute force more evenly across sarcolemma, important because not all of sarcomeres are shortening at same time so this will cause pulling of muscle in different directions, having these proteins helps distribute force, SO WITHOUT it we get localized areas that experience more strain that damages MUSCLE FIBERS
SARGOGLYCAN dfect: limb girdle
Laminin defect: congenital
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Idiopathic (destructive myopathy)
polymyositis and dematomyositis is more comon
-result of AUTOIMMUNE process (inflammatory cells infiltrates (lymphocytes and macro[haces)
-females more than males
-massive desctruction and necrosis of muscle fibers
-decreases miuscle mass, strength, funxtion,
-releases soluble proteins in circulation (CK levels high, urine dark brown from myoglobin from muscles)
-myoglobin can precipitate and block renal tubes and lead to renal failrure
-immunosuprresive durgs used (glucocorticoids) because apoptosis the immmune cells so decrease the response
-remove cells, lots of immuen cell accumulation
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