Physiology Flashcards
cells do not live in isolation they use signalling for
they receive and act on signals from beyond their plasma membrane
-growth
-differntiation and development
-metabolism
when signalling goes wrong
-cancer
-diabetes (islets of langaarhans)
do bacteria signal
-bacteria have membrane proteins that act as information receptors
receptors movement to or from stimulus or formation of spores
plant cells respond to
-variations in sunlight
-growth hormones
-gravity
animals cells respond to
-metabolic activities of neighbouring cells
-place cells during embryogenesis by recognising developmental signals
-exchange info about ion and glucose concentrations
unicellular eukaryotes respond to
-local environment
-mating signals
principles of signalling
1)signal
2)receptor
3)amplification
4)response
ligands that stimulate pathways are called
agonists they are signals
different types of signal
-direct contact = protein(ligand) binds to receptor
-gap junction = exchange small signalling molecules and ions
-autocrine = ligand induces a response only in signalling cycle for example hela cells cam grow on their own due to this EICOSANOIDS = autocrine ligands
-paracrine = the ligand induces a response in target cells close to the signalling cells
endocrine signalling
ligand is produced by endocrine cells and is carried in the blood inducing a response in distant target cells the ligands are often called hormones
paracrine example
acetylecholine as its released into a neuromuscular junction
specificity is provided by two mechanisms
-certain receptors are only on certain cells
-molecules downstream of the receptor only present in some cells
developmental controls
specify which genes are expressed in which cell type genes can be turned on or off by interaction of positive/agitators and negative repressor/regulators with enhancer or silencer control elements
specificity is linked to affinity
-molecular complementarity between ligand and receptor
association rate definition and formula
since there are two reactants the reaction is second order and the rate at which it occurs is determined by concentrations of both reactants and by a constant K+
association rate = K+[R][L]
R = receptor and L = ligand
K+ units
M^-1s^-1 per molar per second
dissociation rate
determined by first order and the rate at which it occurs is determined by concentrations of this reactant and by constant K
Dissociation rate = K_[RL]
K_ units
S^-1
K+ ad K_ are equal therefore
Keq = [Rl]/[E][L] M^-1 this gives the affinity
he dissociation equilibrium equation
Kd = k_/k+ or flip and get k+/k_ (M)
key principle of binding
it is dynamic a mixture of association and dissociation
signalling are amplified
by enzyme cascades which can amplify several orders of magnitude within MILISECONDS
signalling :desensitisation
-when a signal is present continuously the signal transduction pathway becomes desensitised and when it falls below a threshold the system regains sensitivity
signalling :cross-talk
-most signalling pathways share common components leading to potential cross talk
signalling :integration
-if multiple signals are given the cell produces a unified response( a combo of both)
some receptors are enzymes for example
insulin receptor (IR)
insulin
lowers blood sugar levels
what do epinephrine and cortisol do
epinephrine: raises blood sugar levels
cortisol : raises
islets of langerhaans what each one does
alpha:glucagon
beta:insulin
delta:somatostatin
the insulin receptor
Following translation, the receptor subunits:
1 enter the ER (endoplasmic reticulum) membrane,
2 associate into dimers,
3 and are exported to the cell surface, via the Golgi complex.
4 During intracellular transport, the proteins are processed by cleavage, each into an α and a β subunit.
5 At the plasma membrane, they are displayed as trans-membrane proteins
insulin signalling starts at the plasma membrane …
stimulates an allosteric change in IR bringing the cytosolic domains close allowing activation
insulin signalling first step
-activated IR phosphorylates and activates the insulin receptor substrate
insulin signalling adaptor proteins Grb2 and Sos
Activated IRS-1 is bound by the adaptor molecules Grb2 and Sos.
Insulin signalling: recruitment of Ras
Sos converts inactive (GDP-bound) Ras to active (GTP-bound) Ras.
Insulin signalling; signal transduction and amplification
Activated Ras recruits Raf kinase to the membrane and activates its protein kinase activity. RAF phosphorylates and activates MEK kinase. MEK phosphorylates and activates mitogen- activated protein kinase (MAPK).
The adaptors Grb2 and Sos are common to both EGF and insulin signalling, so activation of EGFR and IR recruits the same MAPK cascade … which means the same genes are modulated in the downstream response.
insulin receptors and glucose regulation
IRS-1 is bi-functional.
It also recruits and activates phosphoinositide 3-kinase (PI-3K) to the cytosolic face of the plasma membrane
PIP3 is a second messenger.
First messenger/primary messenger/ligand:
an extracellular substance (for examples, the hormone epinephrine or the neurotransmitter serotonin) that binds to a cell-surface receptor and initiates signal transduction that results in a change in intracellular activity
second messenger:
a small metabolically unique molecule, not a protein, whose concentrations can change rapidly. Second messengers relay signals from receptors to target molecules in the cytoplasm or nucleus.
glucose regulation and PIP
-PIP3 recruits PDK1 (PIP3-dependent protein kinase).
-PDK1 activates protein kinase B (PKB). NB! Care…PKB is also called Akt. The terminology can be confusing.
How/why does IR signal through two pathways?
Why?
A rationale: there’s not much point in growing if there is no food supply.
Do all cells respond to both pathways?
No: terminally-differentiated cells do not respond to the growth signal because of loss of signalling chain components.
Which cells regard insulin as a growth factor? Fibroblasts are the best example.
cellular responses to insulin WITHIN HOURS
- increased expression of liver enzymes that synthesise glycogen
- increased expression of adipocyte enzymes that synthesise triacylglycerols
- increased expression of genes involved in mitogenesis in some cell lines
Termination of the fast Ras-independent pathway
A PIP3-specific phosphatase (PTEN) removes the phosphate at the 3 position of PIP3 to convert it into PIP2. PDKI and PKB can no longer be recruited to the plasma membrane, shutting off signalling through PKB.
Lim et al 2011 type II diabetes
-normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
-Patients increased their exercise levels and ate a VERY restricted diet of ~600 kcal (600 Cal) per day for 2 months
-25% of patients were unable to maintain this lifestyle change
Of the remaining 75% …
… in all cases, weight loss was accompanied by
a possible rewiring of the brain (?) – salads looked like food a reduction in diabetic symptoms
a restoration of insulin sensitivity
BMI 1835 Adolphe quetelet
weight/(height x height)
>30 obese
< 25 normal
the lipostat theory 1953
-postualtes that eating behaviour is inhibited when body weight exceeds a certain value
-postulates that energy consumption increases above set point THEREFORE restriction of eating and more exercise should reduce body mass BUT the opposite happens feedback stimulates eating behaviour when adipose tissue is lost
evidece for lipostat
-soluble factor called leptin is released into bloodstream by adipose
-leptin binds to receptors in hypothalamus
ENDOCRINE due to action at DISTANCE
leptin discovery
identified in mice product of Lep^OB gene (obese)
the number and she of adipocytes is increased in Lep^ob/lep^ob mice
the leptin receptor is the product of
the Lepr^DB gene expressed in hypothalamus
what does leptin do
-released by adipose tissues
-releases Alpha-Melanocyte stimulating hormone that modulates nervous transmission
effects,
-suppressed appetite
-sympathetic nervous system
-increased BP/HR and thermogeneisis
janus kinase(JAK)
cytosolic non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
have two almost identical phosphate transferring domains
erythropoietin (EPO)
hormone cytokine that controls the development of erythrocytes RBCs from precursor cells in the bone marrow
used for aneamia in RARE cases
G-protein coupled receptor (GPCR) structure
-7 transmembrane domains snake through membrane
GPCR ligand binding
-fold into tertiary structure barrel which forms cavity in membrane
-cavity is ligand-binding domain for small ligands
ligand binding CHANGES THE RELATIVE OIENTATIONS OF the TM helices (twisting motion)
GPCR conformational change
-ligand binding alters the conformation of the TM domains and reveals amino acids in teh cytosolic domains for activating heterotrimeric G-proteins
GPCR bound to heterotrimeric G protein
-as it is a trimer of alpha, beta and gamma subunits that is inactive when bound to GDP but active when bound to GTP
-ligand binding alters receptor shape which induces nucleotide exchange the replacement of GDP of the G alpha with GTP
GPCR dissociation
-following G alpha activation the G-protein dissociates from the receptor to yield a G alpha-GTP monomer and a tightly interacting G beta gamma dimer
-these now modulate the activity of other intracellular proteins
GPCR regulation
-G alpha has slow GTP hydrolysis activity this regenerates the inactive form of the alpha subunit allowing reassociation with G beta gamma dimer to form the resting G-protein which can again bind to GPCR and await activation
Flight or fight? Hormones
cortisol
-increases blood sugar through gluconeogensis
-suppresses immune system
epinephrine
-adrenergic receptors (GPCRs)
cAMP is a second messenger
-epinephrine binds beta adrenergic GPCR receptor, G alphas is activated and stimulates adenylate cyclase
-result is increase in cAMP levels in the cell
effects of cAMP
-protein kinase A (PKA) which affects transcription factors, ion channels and a variety of other enzymes
pathways with cAMP are usually given same response
therefore epinephrine and glucagon both raise blood glucose levels and induce triglyceride breakdown
light reception
-in the vertebrate eye, light passes through the neural layer
-through the cell bodies of the light receptor cells (rods and cones) and acts as a signal in the discs of photoreceptive membrane in the outer segment of the retina
light receptors
-inner and outer segments of a photoreceptor cell is a primary cilium(act as signals)
rod cells discs
-the outer segment contains 1000 discs not connected to plasma membrane
-each is a closed sac of membrane with embedded photosensitive rhodopsin molecules
rhodopsin STRUCTURE
a visual pigment specialised GPCR made of
-opsin (GPCR component) linked to 11-cis-retinal a prosthetic chromophore
retinal and light capture cis-trans isomerisation
1)alternating single and double bonds form polyene with a long unsaturated network of electrons that can absorb light energy
2)light absorption causes cis-trans isomerisation around the C12 and C13 bond
3)the N of the key lysine moves 0.5 nm
LIGHT ENERGY IS CONVERTED INTO ATOMIC MOTION WITHIN A FEW PICOSECONDS
light capture: activation of the GPCR
-light absorption by retinal alters the conformation of GPCR (inactive rhodopsin becomes activated metarhodopsin II WHICH stimulates nucleotide exchange on teh alpha subunit of a specific heterotrimeric G protein called transducin (Gt)
the cGMP-gated ion channels close
-hyperpolrising the membrane . a light stimulus has been converted to a change in the electrical charge (potential) across a membrane
rhodopsin sensitivity and insensitivity
peak absorbance 500 nm
rod cell can respond to a single photon
about 5 such responses lead the brain to register a flash of light
light closes the cGMP gated ion channels reducing influx of Ca++
-Ca++ is extruded by Na+/Ca++ anti porters therefore Ca++ concentrations in the cell fall if low enough granulate cyclase is activated causing cGMP to rise again
light activated rhodopsin can be phosphorylated by
rhodopsin kinase
-therefore more light = more phosphorylation
rhodopsin: very light insensitivity (SUMMER NOON)
-arrestin binds to fully phosphorylated rhodopsin and this stops activation of transducin
-Rhodopsin kinase and arresting also inhibit other GPCRs not just rhodopsin
3 mechanisms that make rods insensitive to light
-prolonged cGMP gated channel closure
-phosphorylation of opsin reduces transducin activation
-arrestin binding to phosphorylated opsin stops transducin activation
trichromatic
3 visual pigments
human colour vision relies on three visual pigments
-412-426 nm
-530-532 nm
-560-563 nm
monochromatic vision
-an opsin (modified GPCR) with
-11 cis-retinal as the chromophore and there is a different transducin
colour tuning
-amino acid differences in the trans-membrane segments of the protein component alter the electronic environment that surrounds the 11-cis-retinal chromophore
what di birds see peacocks
-7 year Japanese study concluded that female choice was not influenced by peacock tails birds have a WIDER spectrum than us therefore we cannot make assumptions based off of our eye sight
cephalopod (octopus eye) vs human eye
cephalopod
-light strikes retina directly vs indirectly
-no blind spot
-retina only has rod cells
John dalton 1766-1844 hypothesis
colour blind and postulated that the vitreous humour in his eyes was tinged blue that absorbed red light and that people with clear vision must have clear humous in eyes
clout blindness genetic mutational causes
-whole colour spectrum is altered
selective pressure for human trichromacy
-did human vision coevolve with production of colours in maturing fruit
1777: report of people with defective vision very poor at slecting ripe fruit
so shouldn’t dichromate have a selective disadvantage or does it help them spot other things
summer 1940 US camouflage planes
-one colourblind observer spotted all 40 planes compared to observer who spotted 10
sildenafil citrate
-second most successful drug of all time
-similar structure to cGMP therefore it is a inhibitor of cGMP phosphodiesterase SIDE EFFECT blue tinged vision
nitric oxide and signalling
1847
-nitroglycerine (NG) was discovered by Ascanio sobrero in Turin. He noted the violent headache produced by minuet quantities of NG on tongue
-NG was used as a headache cure a homeopathic use
-1867 brunt used AMYL NITRATE to relieve angina
-1876 Murrell tried NG for angina and used a more stable version
how does nitric oxide signal? it activates guanlyate cyclase
-soluble gas that can diffuse across membrane
-binds to guanalyte cyclase synthesises cGMP teh second messenger altering the activity of target proteins
1)the gas NO
2)Diffusion
3)activates its receptor
4)activated receptor (GC) converts GTP into cGMP
5)cGMP is a second messenger that alters the activity of target proteins
nitric oxide is written as NO* because
it has a free radical (unpaired electron)
Angina treatment today
-glycerol trinitrate remains the treatment of choice
-other organic esters and inorganic nitrates are also used
NO* production in vivo is stimulated by high BP
1)autonomous nerves in the vessel wall respond to high BP and release acetylcholine (Ach)
2)acetylcholine binds its receptors (AchR) on the membrane of endothelial cells
NO* production in vivo is stimulated by high blood pressure
Increased [Ca++] and nitric oxide synthase
-Ca++ is a second messenger
-high Ca++ activates nitric oxide synthase (NOS)
-NOS catalyses the conversion of arginine to citrulline and nitric oxide
NO* now acts as a paracrine signal to smooth muscle
NO* is unstable.
It is converted to nitrate and nitrite within 10 seconds.
This short life means it can communicate only over short distances (paracrine signalling, neighbouring cells).
NO* activates soluble guanylate cyclase by binding to its haem group, causing a conformational change.
GC converts GTP to cGMP
cGMP is a second messenger
cGMP activates protein kinase G in smooth muscle
PKG is a cGMP-dependent protein kinase.
It phosphorylates myosin light chain.
Muscle cells with phosphorylated myosin light chain relax.
Smooth muscle relaxation causes dilation of the blood vessel.
Dilation increases the volume of the vessel and lowers blood pressure.
other sources of NO* and its effect
-an amyl nitrate inhalation spray is commonly prescribed for a weak heart
-it vaporises to generate NO* which dilates vascular model
Cyclic nucleotides and PDE5
-cyclic nucleotides are important secondary messengers that control many physiologic processes including smooth muscle contractillity
-phosphodiesterases (PDEs) a superfamily of that cleave 3’,5’-cyclic phosphate
sildenafil citrate/ viagra is
cGMP mimic
-potent inhibitor of cGMP phosphodiesterases
-most active against phosphodiesterase 5
oestrogen and the oestrogen receptors (ERs)
-4 types on poster
-steroid hormones synthesised from androgens(male sex hormones)
-oestrogen receptors written as estrogen
the ER is cytosolic
-the ER has an N-terminal transactivation domain, a DNA binding domain, and a hormone binding domain that can bind oestrogens
-it is stored in the cytosol in complex with a dimeric chaperone protein called Hsp90
-it binds near the ligand-binding site and maintains the ER in a soluble state (COMPLEX TOO LARGE TO ENTER THE NUCLEUS)
Steroid hormone signalling is unusual: no amplification
The ER is the receptor for oestrogen.
Oestrogen-activated ER binds DNA and directs transcription of oestrogen-response genes.
This means that ONE protein is both receptor and effector. There are no amplification steps via protein cascades or via second messengers.
Steroid hormone signalling is unusual: no amplification
The same is true of other steroid hormone receptors – and the receptors for thyroxine and retinoic acid.
there are multiple isoforms of the ER
-two different forms alpha and beta each encoded by a separate gene
-plus splicing variants large combinational repitoire
what does the nervous system do?
1)receive and interpret information about the internal and external environments of the body
2)make decisions about the information integrating system
3)to organise and carry out action motor system
neuron doctrine (circa 1894) With Golgi body stain
The neuron is the structural and functional unit of the nervous system
Neurons are individual cells, which are not continuous to other neurons
The neuron has three parts: dendrites, soma (cell body) and axon
Conduction takes place in the direction from dendrites to soma, to the end
arborisations of the axon
how should we classify neurones?
-morphology
-internuerones
-neurotransmitter
Anterograde transport
WGA-HRP)
From soma, down axon to terminals
Two kinds: rapid: 300-400 mm/day
(up to 1 μm/s)
slow: 5-10 mm/day
Retrograde transport
(HRP)
From terminals to soma
Worn out mitochondria, SER
Rapid: 150 - 200 mm/day
encephalisation quotient
=brain weight/ body weight
expected linear relationship with sharks through frogs but but gyri makes brain smaller
brain structures defined by embryology
4 weeks
Prosencephalon
Forebrain
Mesencephalon
Midbrain
Rhombencephalon
Hindbrain
6 weeks
Prosencephalon:
Diencephalon
Telencephalon
the meninges
-surround the CNS
-brain surrounded by cerebrospinal fluid
3 layers
1)tough outer layer
2)arachnoid mater
3)pia mater
the ventricular system
Principle source of CSF: choroid plexuses in ventricles
About 150 ml CSF
25 ml in ventricles
125 ml in subarachnoid
spaces in brain & sp cord
Renewed ~ 4-5 times in 24 hrs
Removes waste products
Supplies brain & sp cord with nutrients
Buffers changes in blood pressure and protects brain
Supplies brain with fluid during dehydration
Allows the brain to remain buoyant
The motor-sensory homunculus redrawn
Homunculus derived from the vertical length measurements. (D) Homunculus derived from the number of stimulation points
intracellular glass microelectrodes
-cells are very small so hard to get inside
-first glass micro electrodes LING and GERARD 1949
making the membrane potential more negative is
hyperpolarising
making the membrane potential more positive is
depolarising
resting membrane potential requires
JULIUS BERNSTEIN 1880s
-intact cell membrane
-ionic concentration gradients and ionic permeabilities
-over the long term metabolic processes
at equilibrium there is a balance between
K+ ions moving in and out of the cell which occurs at the resting potential
how membrane potential changes with extracellular [K+] if membrane is only permeable to K+ ions
-reduces electrical gradient to balance
-as we increase K+ concentration outside cell membrane potential becomes depolarised
rising phase of action potential due to Na+ influx
-found action potential needs Na as less Na lower action potential make
Na+ channels allow influx of Na+
Voltage-gated channels: transmembrane proteins
Activated by changes in voltage (depolarisation)
Selective for ionic species eg Na+, K+, Ca2+ etc
What initially depolarises neurones to open
the voltage-gated Na+ channels?
Synaptic transmission: excitatory postsynaptic potentials EPSPs
Generator (receptor) potentials (sensory neurones)
Intrinsic properties (eg pacemaker activity in heart)
Experimental (eg electrical stimulation)
Ion flow during the action potential
Around threshold Vm, the membrane becomes much more permeable to Na+ ions
This leads to depolarisation and further recruitment of VG Na+ channels
Depolarisation results in VG Na+ channels inactivation (closure)
After a delay VG K+ channels open
Both contribute to the repolarisation of the membrane after the action potential
two things contribute to repolarisation
1)Na+ channels close
2)voltage-gated K+ Chanels open
concentration gradient outward: 125 mM inside 5 mM K+ outside
electrical gradient outward: positive
THEREFORE K+ MOVES OUT OF NEURON
voltage gated Na+ channel inactivation
ball and chain model
1)positively charged activation gate keeps channel closed
2)depolarisation of membrane causes activation gate to swing out of the way allowing Na+ ions to enter and cause further depolarisation
3)the inactivation “ball” rapidly enters the channel to block Na+ influx
refractory periods absolute vs relative
-The absolute refractory period (ARP) starts from when VG Na+ channels open and continues for ~1 ms.
-During this time it is not possible to elicit another action potential
-The ARP is due to VG Na+ channel inactivation.
-The relative refractory period (RRP) continues for 2–3 ms after the ARP
-Action potentials can be elicited, but requires stronger or longer stimulation.
-The increased K+ permeability during the RRP makes it harder to depolarise the membrane to activate VG Na+ channels and elicit an action potential.
action potentials are initiated at the axon
hillock
bigger axon diameter =
faster conduction
Myelination greatly accelerates action potential velocity
saltatory conduction
synaptic cleft is
20-40 nm wide
sicles are
40-50 nm
axodendritic synapses
synapses that one neuron makes onto the dendrite of another neuron.
how is neurotransmitter packaged in vesicles
A non-peptide neurotransmitter is
synthesized in the nerve terminal
and transported into a vesicle
-proton gradient drives vesicle filling
neurotransmitter release
4 basic steps
1. Docking/priming
2. Ca2+ entry
3. Vesicle fusion (exocytosis)
4. Recycling of vesicles (endocytosis
neurotransmitter release 1)docking of vesicles to membrane
1)docking of vesicles to membrane
-combo of SNAP and SNARE proteins anchor vesicles to the presynaptic membrane
-docked vesicles are ready to release their contents
neurotransmitter release 2) Ca 2+ entry into nerve terminals
The action potential:
1) depolarises nerve terminal via voltage-gated Na+ channels
2) opens voltage-gated Ca2+ channels
3) Ca2+ moves into the nerve terminal down its electrochemical gradient into the neuron
neurotransmitter release 3)Ca2+ entry leads to fusion of docked vesicles
and release of neurotransmitter (exocytosis)
Ca2+ binds to one of the SNARE proteins (synaptotagmin, is the Ca2+ sensor )
Important features of Ca2+-dependent neurotransmitter release
Neurotransmitter release requires binding of multiple Ca2+ ions (between 3 to 5).
Neurotransmitter release occurs very quickly after Ca2+ entry
Blocking Ca2+ entry blocks synaptic transmission (cadmium and toxins from spiders/snails)
Knockout of synaptotagmins: lose fast synchronous neurotransmitter release
neurotransmitter release 4) endocytosis (vesicle recycling
Blocking endocytosis (eg with Dynasore, which inhibits dynamin) leads to rapid synaptic depression
Identifying a substance as a neurotransmitter
- Must be synthesised in the neuron
- Show activity-dependent release from terminals
- Duplicate effects of stimulation when applied exogenously
- Actions blocked by competitive antagonists in a concentration-dependent manner
- Be removed from the synaptic cleft by specific mechanisms
somatic nervous system
voluntary movement
in humans there are __ pairs of spinal nerves
31
white matter:
-axonal tracts
-ascending and descending
-motor and sensory
dorsal grips carry info to
the dorsal part (back) of spinal cord
ventral spinal cord
ventral (which means “towards the stomach”)
nerves are multiple
nuerons and can be bungled together in fasicles
upper and lower motorneurones
UMN are in spinal cord and LMN in muscle
gyrus
part of Brain that sticks up
sulcus
dips down
corticospinal pathway
is the major neuronal pathway providing voluntary motor function. This tract connects the cortex to the spinal cord to enable movement of the distal extremities
motor units
neuromuscular junctions or motor end-plates
muscle fibres and single motor neuron
motor units
different sizes
-when a motor neuron is activated all the muscle fibres that it innervates contract
-motor units are intermingled throughout muscles
-dine control = small motor units
-coarse control = large motor units (2000 muscle fibres)
motor units contain Differnt types of skeletal muscle type 1:
Slow oxidative (ATP oxidative phosphorylation)
Speed of contraction: slow
Force generated: low
Small motor units
skeletal muscle type 2
Fast oxidative (ATP oxidative phosphorylation)
Speed of contraction: intermediate
Force generated: intermediate
Intermediate motor units
Fast glycolytic (ATP through glycolysis)
Speed of contraction: fast
Force generated: high
Large motor units
neurotransmitter and nicotinic
Acetylcholine activates
nicotinic receptors on muscle
Nicotinic receptors are
ion channels (inotropic)
Permeable to Na+, K+ and Ca2+
Depolarise muscle fibres
single contraction of muscle is
twitch
increasing force of contraction through a few steps
1) recruitment = smaller motor units recruited first(lower threshold)
2)temporal summation = twitches dont have time to decay therefore they get bigger
unfused vs fused tetanus
unfused has small time to relax
some muscles show fatigue
less muscle tension each time
Why do muscles show fatigue?
-Protective/ defence mechanism
Causes
Depletion of glycogen
Accumulation of extracellular K+
Accumulation of lactate
Accumulation of ADP + Pi
Central fatigue
tendon organs in muscle
detect how much the muscle has contracted and tells brain
muscle spindles
tell brain how much muscles have stretched
-intra/extrafusal
