Neuropathies
-a neural defect in getting the signal to the muscle
-muscle cannot function without an intact nerve supply
THEREFORE, loss or improper function of the nerve supplying the muscle leads to muscular dysfunction
-if nerve supply is altered, the fiber change or be lost regardless of fiber type
In neuropathies, what leads to muscle dysfunction
a loss or improper function of the nerve supplying the muscle leads to muscle dysfunction
what happens if the fiber is denervated and reinnervated
transition from slow to fast fibers, ue to decreased activity
-ie an existing motor neuron will sprout out an axon and reinnervate the muscle that lost the motor neuron, so there is an initial change from slow to fast (because there was originally a lack of activity)
What is small group atrophy
-small group of motor units are effected, therefore some fibers are atrophic, some are hypertrophied (As they are non affected fibers), this indicates a loss of few motor units
-looks like some fibers are much larger in siz, some are smaller
-affects some motor units but not others
Large group atrophy
-extensive atrophic fibers within a fasicle
-almost all fibers are effected
Denervation in general
-loss of neural activity leads to increase in reversal of developmental processes, ie the muscle goes backt o the state before it was developed
- NCAM (neural cell adhesion molecue) is upregulated
- to reestablish nerve supply
-axons sporut from nearby undamaged motor neurons and branch to form new contacts with the unnerved muscle fibers
SLOW PROCESS SO LOSS OF FXN AND ATROPHY OCCURS until reinneveration is done
-myonuclei also lose shape and become centralized
-mitochon become smaller because metabolic activity need is decreased so they dont need alot or big mito anymore since there is no funxtion
Reinnervation: fiber type Grouping
healthy muscle has random distribution of different fiber types
WHEN REINNERVATED: the muscle that is getting inervated becomes the fiber type of the neuron that it is getting innervated by
“fiber type grouping”, essentially it ends up being that similar fiber types are all grouped together because the neuron near it is now innervating it making it the same fiber type so now muscle looks very grouped in its fiber types
Spinal Cord Injury
muscle atrophy in all fiber types
SWITCH from slow to fast as well
What are individuals with malignant hypothermia really sensitive to
anesthetic halothane
or stressful situations
Conditions with Normal Muscle Mass
-means not associated with loss of muscle mass
-relatively rare griup of conditions
-general symptoms include
a) rapid onset fatigue
b) abnormally long contractions
c) episodes of brief paralysis
two groups: a) channelopathies and b) metabolic myopathies
A) CHANNELOPATHIES
-remember, proper muscle function requires proper function of ION CHANNELS in muscle so diseases that effect the structure or function of these channels have BIG impact on muscle function
3 most common channelopathies are:
1) malignant hyperthermia
-caused by 20 mutations of Ryanodine receptor (remember this is a calcium channel on the sarcoplasmic reticulum that lets it into the cytosol for contraction)
-these indiv are very sensitive to anesthetic HALOTHANE (some to stressful situations)
-BOTH results in prolonged release of CA from RYR receptor so therefore PROLONGED CONTRACTION, METABOLIC SUBSTRATE DEPLETION, And MUSCLE DAMAGE
-renal failure due to myoglobin release
- a similar disease is found in danish PIGS to produce VERY LEAN MEAT (happens when stressed or response to anestheric halothane)
2) myotonia
-defect in gene for Cl- channel
-Chlorine channel is for reducing/ stabilizing resting membrane potenital after muscle action potential (essentially helps repolarize the membrane after excitability, important for ensuring that contraction ends)
-it controls ion gradient between muscle membrane and extracellular fluid)
-for this channelopathy, it does not work problem so membrane remains in an excitable state for an extended period of time because repolarization does not occur so HYPERPOLARIZED)
-leads to prolonged contraction up to 30 seconds
-first seen in FAINTING GOATS that would fall over with rigid muscles when startled
3) Hyperkalaemic periodic paralysis
-defect in SODIUM CHANNEL
-channels stop funxtioning during EXCITATION and REMAIN OPEN
-usual purpose is to depolarize quickly and then close so that muscle can repolarize and prepare for next contraction
-in defect: continued Na influx, and muscle remains depolarized, so abnormal REFRACTORY STATE (so cannot and willl not respond properly to signal so not ready for subsequent excitation)
-results in periodic paralysis anf is associated with hyperkalemia (high K+ in bloo) because it moves to blood to try and repolarize the membrane (because usually it goes out of cell to repolarize after depolarize but since this is really depolarized, it needs more K+ out which increases levels)
B) METABOLIC MYOPATHIES
-muscle contraction places demand on metabolic pathways due to increased need for ATP
-when resting, these individuals wll have normal strength and function HOWEVER< when exercise, disease shows
i) glycogenoses
-defects in the enzymes of the glycolytic pathway
-normally associated with abnormal ACCUMULATION OF GLYCOGEN IN MUSCLE
-lack of enzymes limit exercise capacity (Several fold increase in enzyme activity is needed to maintain energy demands)
-high glycogen can become toxic and damage muscle proteins and membrane, myofibril architecture (which can exert force)
-most studied is MCARDLE
-glycogen storage in muscle occurs when there is a deficiently in glycolytic enzymes
MCARDLE:
-low intensity workout fine, higher intensite results in muscle fatigue withint seconds-minutes after ATP-Pcr stores and blood glucose are depleted (Cant use glycogen in phosphorylase deficiency), these twoa re used because the rate at which we need atp is high so we cant use oxidative ones because our rate at getting o2 there is slower
-muscle fatigue with little lactate accumulation
-cant use proteins or fats here because it takes long and reqwuires oxygen, in high intensity situation ATP needs are higher and OXYGEN is limiting so it ends up being more ANAROEBIC), low intensity atp rate is low, atp need at high is HIGHER RATE so oxygen is limiting because rate of getting o2 to muscle is slow
-painful muscle contractures (fatigue and contractures are due to atp depletion , if atp not there , myosin will be bound to actin so it wont move, just be contracted like that, decreased ca2+ pump (serca needs atp) activity due to fall in atp content in critical intracellular compartments), this elevated Ca can lead to caspase activation (proteolytic enzyme) and signal APOPTOSIS)
ii) Mitochondria myopthies
-includes disorders which show defects in mito funx
-indiv have limited exercise capacity, mild activity even leads to breathlessness and severe metabolic acidosis
-very pronounced in long duration exercise
-increases in lactate because glycolytiv wotks fine so this means that it can be overworked to the point of lactate acidosis! problem here remember is in aerobic met, that is why they cannot do long activity because aerobic provides most of atp
-CAN BE MANT TYPES: ie problem in substrate transport (now we cant use this substrate to make atp), or problems in substrate utilization (similar as other one), problems in respiratory chain (etc chain, cant make atp), defects in energy conservation and transduction (maybe atp synthase doesnt convert it properly, or it cant leave to be used)
-effect 1:8000 individuals
nuc dna and mito dna are important for etc and mito
-specific gene mutations have been seen in nDNA and mtDNA for patients with mito myopathies
-most common and studied: ETC effecting mitochon myopathies
a) Abnormal mitochondria:
patients with defects in complex 1 have abnormal mito proliferation (compensate for ETC dysfunction).
-mito accumulates in edges of fibers and appear RED with TRICHOME STAIN (ragged red fibers)
-1-40% of fibers frequency range
WHY MIGHT EVERY FIBER NOT BE EQUALLY EFFECTED:
-mito dna is not the same in every fiber , so we can have one fiber that has alot of defect but one doesnt
-mito dna is not the same as reg dna, nuc dna (if one has it all does because nuc dna is exact copy)
-if they enherited the same mito dna, why might thry still be different: remmeber when in energy deficit, the cell tried to overcome this by making more mito so more mito enzymes, this is where recruitment patterns come in: if we use it more, they will see energy requirement need more and this will show differences in this fiber compared to another even though they may have the same dna.
-these individuals have PARACRYSTALLINE INCLUSIONS composed of mt creatine kinase shows lots of proliferation and mtCK. (may look like it will have benefits because can make more atp, but eventually it crystalizes and cant function)
-BASICALLYYY indivifual tries to do work, there is energy demand, needs more atp, so to solve, they make more mito BUT problem is we have defect so as we make more mito it becomes paracrystalline inclusions and it does not work anymore so just accumulate with no funxtion)
WHy does the system try to increase the creatine kinase?
-everything that we need atp for is in cytosol, so we need to move atp out. Atp can diffuse out but its pretty big so its hard so instead we use creatine kinase and atp to make phosphocreatine that can be transported out easier. PCr then gets converted to ATP in cytosol.
-PCr is used more due to energy demand
-more mitochondrial creatine kinase would increase PCr and PCr transport out of mito, which would then make the atp outside
-wuicker than atp transport. System knows this so it makes alot of creatine kinase so that it can bump up this transport. but when we get alot of these in a small space, they aggregate adn crystalize, forming the PARACRYSTALINE INCLUSIONS. IF THERE WAS NO ENERGY CRISES THE CELL WOULDNT DO THIS.
b) DISORDERS OF FAT METABOLISM
-dysfunction or deficiency in Carnitine or Carnitine palmitoyl transferase (CPT ENZYME)
-lacking carnitine or carnitine palmityol transferase causes muscle weak, pain, and damage during exercise (ATP DEPLETION, ACIDOSIS, ELEVATED CA+)
-muscle biopsies show LARGE FAT DROPLETS
-can disrupt myofibril architecture.
i) Abnormal lipid accumulation
-lipid droplet bigger than Z disks
-fat accumulates INSIDE CELL
-some fibers might be more metabollicaly active so lipid would be different size
-each fiber is affected differently
c) COPD and Chronic heart Failure
COPD: disease of lungs that makes breathing difficult, chronic bronchitis, and emphasema
CHF:
-caused by conditions that DAMAGE HEART (hypertension, myocardial infection, etc)
-condition where funxtion or structural changes impair the ability of heart to fill with or pump BLOOD to body
Both are conditions of other organs but they can affect skeletal fiber because they supply muscle with nutrients, oxygen, signalling molecules, to function properly so local or systemic inflammation will effect it
How are muscles changes in COPD and CHF:
-atrophy of type 1 and type 2 but more type 1
-change in fiber type: less type 1 (loss of type 1, 1->2 shift)
-reduced oxidative capacity (mito content an oxidative enzymes are reduced, and decreased capillary density and myoglobin)
-SDH AND CS reduced so cant make atp aerobically that well
-lower resting and exercise ATP, PCr, and glycogen conc
what does malignant hyperthermia result in
prolonged contraction
metabolic substrate depletion
muscle damage
also risk of renal failure due to myoglobin release
What are the stages in an Action Potential
resting: cell is negative compared to outside
1) Depolarization: membrane depolarizes to threshold by stimulus and this opens Na channels. Na enters cell and this causes increase in Na and this rapid entry DEPOLARIZES CELL (voltage gates K+ also open adn it slowly leaves)
2) NA CHANNELS CLOSE AT TOP OF PEAK and slower K+ channels open REALLY OPEN HERE
3) K+ moves out of cell into extracellular fluid (REPOLARIZATION), downhill
4) K+ remains open as they are slow to close and this hyperpolarizes the cell (makes it more neg than resting)
5) k+ channel closes adn it Na/k+ pump is now regular ad back at resting potential for ce;l now.
READY FOR ANOTHER AXTION p
Failure of EC-Coupling: Channelopathies
pictures
SO THINK ABOUT IT
for myotonia: it is continous contraction
for periodic paralysis: it is not
What is the energt investment phase of glycolysis
USING ATP TO MAKE MORE LATER
Glycogen broken down by PHOSPHORYLASE to eventually be g6p ORRRRR glycose uses one atp and with HEXOKINASE becomes g6p
THENNN Phosphofructokinase uses 1 atp to break down fructose6phosphate to fructose 1-6 biphosphate
so if starting with glucose 2 atp used
if starting with glycogen then 1
check slide 49 in lec 1
what is glycogenoses
i) glycogenoses
-defects in the enzymes of the glycolytic pathway
-normally associated with abnormal ACCUMULATION OF GLYCOGEN IN MUSCLE
-lack of enzymes limit exercise capacity (Several fold increase in enzyme activity is needed to maintain energy demands)
-high glycogen can become toxic and damage muscle proteins and membrane, myofibril architecture (which can exert force)
-most studied is MCARDLE
-glycogen storage in muscle occurs when there is a deficiently in glycolytic enzymes
Mcardle disease
MCARDLE:
-low intensity workout fine, higher intensite results in muscle fatigue withint seconds-minutes after ATP-Pcr stores and blood glucose are depleted (Cant use glycogen in phosphorylase deficiency), these twoa re used because the rate at which we need atp is high so we cant use oxidative ones because our rate at getting o2 there is slower
-muscle fatigue with little lactate accumulation
-cant use proteins or fats here because it takes long and reqwuires oxygen, in high intensity situation ATP needs are higher and OXYGEN is limiting so it ends up being more ANAROEBIC), low intensity atp rate is low, atp need at high is HIGHER RATE so oxygen is limiting because rate of getting o2 to muscle is slow
-painful muscle contractures (fatigue and contractures are due to atp depletion , if atp not there , myosin will be bound to actin so it wont move, just be contracted like that, decreased ca2+ pump (serca needs atp) activity due to fall in atp content in critical intracellular compartments), this elevated Ca can lead to caspase activation (proteolytic enzyme) and signal APOPTOSIS)
what might be a therapy to deal with mcardle
how can we get them to exercise at higher intensity:
-if we work at shorter intervals
-make aerobic metabolism better (increase aerobic enzymes, increase mito so that we can get better Vo2, so o2 delivery is faster adn we can get more atp that way, makes using fats better so we can increase intensity without fatiguing faster) MAKESS SEN!
-problem essentially is:L we cant use glycogen, and when we are in high intensity, we are unable to use aerobic good enough because we cannto get o2 fast enough so we are stuck using anaerobic but this we cant eben do properly because wer cant use glycogen so if we better the aerobic, we can use things like fats to make atp in aerobic rather than relying on only atp-pcr adn anaerobic for the short little bit that it even provides in the first place
ii) Mitochondria myopthies
-includes disorders which show defects in mito funx
-indiv have limited exercise capacity, mild activity even leads to breathlessness and severe metabolic acidosis
-very pronounced in long duration exercise
-increases in lactate because glycolytiv wotks fine so this means that it can be overworked to the point of lactate acidosis! problem here remember is in aerobic met, that is why they cannot do long activity because aerobic provides most of atp
ii) Mitochondria myopthies
-includes disorders which show defects in mito funx
-indiv have limited exercise capacity, mild activity even leads to breathlessness and severe metabolic acidosis
-very pronounced in long duration exercise
-increases in lactate because glycolytiv wotks fine so this means that it can be overworked to the point of lactate acidosis! problem here remember is in aerobic met, that is why they cannot do long activity because aerobic provides most of atp
look at slide 63 in lec 1
potential mechanisms
6 mechanisms are highly implicated to muscle dysfunction and aterophy
1)Decreased satelite cell and function
2) Mito chondria dysfunction and accumulation of Mt DNA mutations
3) INCreased free radical generation and oxidative stress
4) Apoptosis and cell death
5) Autophagy and protein degredation
6) systemic and local inflammation
LEC 4
Tissue Turnover
-for proper growth, cell renewal and reproduction needed
-general mech are similar for all cell types, differ a bit between
-cell death, proliferation and differentiation relationship are imp for tissue turnover and homeostasis, essential for generation n maintenance of complex tissues
