4433 Final Exam

how are satellite cells activated

receive signals that damage has occurred

what signals satellite cells

- myofibre cytosolic proteins
- localized protein factors in the ECM
- paracrine factors from inflammatory cells

what is a marker in the blood that damage has occurred from exercise

CK - creatine kinase

what kind of signal is CK

paracrine

what is chemotaxis

chemical that brings other proteins --\> attracts satellite cells and creates a laneway for cells to focus on a certain area

how do satellite cells repair muscles

- fuse either to each other to form immature myotubes which then differentiate and mature to act as a new muscle fibre
- fuse to the existing fibres and donate their nuclei to create new proteins

what is the pathway from chemotaxis to regenerated myofibre

chemotaxis --\> satellite cells signalled --\> satellite cells fuse together (hyperplasia) or to the muscle (hypertrophy) --\> donate nucleus --\> central nucleus --\> maturation --\> nucleus moves to periphery

how do NSAIDs impact the satellite cell response

suppress inflammatory response which decreases the signal to satellite cells and decreases regeneration

explain satellite response to intense, damaging exercise and its association with CK and soreness (what happens when it is repeated a month later)

- begins to rise 3-4 hours post exercise
- after 72 hours the SC count has risen dramatically
- peak soreness matches peak SC because signals are highest at this point
- CK activity is up steadily up to 96 hours post
- one month after they repeat same exercise and find that soreness is down, so the muscle has adapted to withstand more

what muscles have splitting

cardiac

what is fibre splitting explained by in skeletal muscle

myotubes formed by satellite cells are branched - fibres branch, do not split

how do new nuclei change a muscle cell

- demand more space in the cell and manages a certain volume of sarcoplasm
- respond to signals to change expression of genes thru mRNA

what happens when a muscle fibre is denervated

- from 0-14 days still innervated the muscle grew in size and had more nuclei
- when the muscle is denervated the muscle atrophies and size drops off quickly
- if we switch the nerve type the muscle type can change

what happens when we stop training for period of time

when we stop training we can start and gain muscle bak quickly because the nuclei are kept - period of muscle memory

effects of chronic low frequency stimulation

- mimics contractile frequency of type 1 fibres
- type 2a changes rapidly, quick drop in 2b and increase in 2a
- therefore fibre types can change

how do we know that fibre types can change

when chronically stimulated with low frequency which mimics type 1 stim there is a change from 2b to 2a

effects of radiation and low freq stim on type 1 fibres

- one group had low freq stim and had increased type 1 %
- other group had radiation which kills immature cells and caused the change in type to be halted which means that without satellite cells we would not have this growth

how many MHC do type 1 fibres have

one MHC

what kind of fibres have more than one MHC

hybrid fibres

can a fibre have multiple types along it, how and what are these called

yes
- can start as a type 2a then slowly change over to 2b along the fibre
- called type C - hybrid of 2a and 2b

how do hybrid fibres change with training

switch to one type or other with specific training

what species has the highest number of hybrid fibres, what percent do humans have

rats (39%), humans have 24%

difference in trained vs untrained identical twins

- type 1 higher in trained than untrained
- hybrid cells higher in untrained

why does the untrained twin have more hybrid cells than the trained

training has caused the hybrid cells to differentiate to type 1 based on training

what impacts the which type hybrid cells turn into

type of training (more damage \= increased inflam repsonse)
- light vs heavy load
- slow vs fast speed
- concentric vs eccentric contractions

how long does it take for a muscle fibre to completely recover and mature after damage - what does this process involve

days - nuclei are in the centre, not mature weeks - nuclei migrate to periphery
- involves degeneration and regeneration

how can the inflammatory response be detrimental

over exaggerates injured area, eats some healthy tissue as well as damaged

neutrophils and their function

neutrophils mark the damaged area to show macrophages what to eat

macrophages function

come in after neutrophils to eat the damaged tissue and other tissue marked for death

what is the process of degen and regen

- degen begins after damage
- regen ramps up as degen goes down

when are inflam cells present

within a day of exercise and up to 10 days after

how long does the generation of new myofibres and patching of damaged fibres take

3-10 days

what does the overlap of degen and regen allow for

speeds up recovery process

general role of inflam cells and the process

- macrophages/moncytes and neutrophils arrive at the scene after being signalled by damage
- neutrophils mark the area
- macrophages proliferate and get rid of damage via phagocytosis

what do macrophages eat

fragments of cells, organelles, and proteins and fibres that cannot be repaired

what occurs in the degen phase in terms of collagen

inflam cells get rid of everything except collagen so it leaves kind of a shell for new things to be made in the regen phase

timeline of degen and regen after heavy damage with neutrophils and macrophages

- within a day degen phase begins and neutrophil activity peaks
- macropahges come in and eat marked tissue
- neutrophils decline and regen starts after about 2.5 days

what are the 2 pools of macrophages

- monocytes
- quiescent macrophages

where are monocytes found

circulate in blood

where are quiescent macrophages found

reside in epimysium and perimysium

what stimulates the release of macrophages

- CK release
- broken bits of cells/proteins
- paracrine factors

how do macrophages affect satellite cells

provide cues that guide activation, proliferation, and differentiation of satellite cells

step one--\>4 of macrophage function

1: turn them on
2: gobble up broken bits
3: turn on stellite cells
4: feel the DOMS

what are cytokines

small proteins released from cells that provide paracrine and autocrine signalling

how do cytokines adapt to training

go to tissues to initiate healthy response

what attracts macrophages to damaged tissue

- cellular debris and cystolic proteins

how does the monocyte response change with training

after they are used once they stay in the area and are nearby the next time damage occurs, so they act more quickly

how do macrophages signal satellite cells

macrophages express other cytokines while cleaning up which are received by SC and drive their activation and proliferation (now myoblasts)

What are M1 macrophages?

first group to go to the muscle (come to the muscle or are local) and then activate and replicate within the day

which timeline do M1 macrophages match

DOMS

how long does it take for satellite cell activation and proliferation to increase

2-3 days

what are M2 macrophages

follow the M1s and mature the myoblast into a muscle fibre

timeline of M1 and M2

M1 increase post injury within the day and activate satellite cells which turn into myoblasts in 2-3 days then M2 comes in to mature the cells into functional units

what cells are included in the degen vs regen phase and in their overlap

degen - inflam response: M1, neutrophils
regen - M2
overlap - satellite cells

what is an example of a chronic inflam disorder and what happens to the inflam response how can exercise help

T2D, heart disease
- coordinated reponse becomes chronic and always elevated M1 and 2 and uncoordinated, exercise can help to coordinate
- releases cytokines that go to the heart, bones, vessels to have a positive inflam response

how does the degree of damage imact the inflam repsonse

more severe damage \= longer response and higher magnitude

what happens when we remove neutrophils, can this be done in humans

- mice without neutrophils (CD18 gene knocked out) demonstrate better recovery after exercise
- less injured fibres after 3 days, recovered faster after 7 days was back to full contractile properties
- macrophages can recognize damage by themselves and do not have the marking of healthy tissue
- cannot be done in humans

how do new muscle fibres mature

myotubes --\> proteins --\> CK --\> adrenergic receptors --\> SR and mitochondria developed and expanded

how many days after exercise does it take to get muscle back to size and original strength and how long until fully mature

- 21 days back to post exercise
- 35 days until mostly mature, but still growing (3-4 weeks to full size which is greater than size pre exercise)

what does diabetes cause in terms of muscle size

much smaller muscle size with T1D

why is there a smaller muscle size in those with T1D vs healthy

- lack of ability to repair muscle due to myopathy similar to aging
- after 5 days T1D almost the same
- after 10 days healthy have much greater size
- 21 days healthy have larger fibre size than original, T1D still much smaller
- 35 days post T1d back to original, but never pass it
--\> lack of response due to increased collagen makes it difficult for nerves to move around

what is the embryonic MHC and its characteristics

undifferentiated MHC that can turn into any type of muscle

what is happening with embryonic MHC 5 days post exercise vs 10 days post

- 5 days post lots of EMHC
- 10 days post EMHC no longer there, being replaced with differentiated MHC which is dictated by external signals

what can cause the differentiation of eMHC

alpha motor neuron types

what happens with eMHC after exercise to turn it into a type 1 fibre

- transitions to type 2 without innervation it will stay this way
- type 2 changes to type 1 if innervated by a type 1 alpha motor neuron

what is the role of training in eMHC differentiation

without training eMHC will turn into type 2 fibres, with training the innervation can change it to type 1
- therefore training can change fibre types

what happens when a muscles fibres swap innervation

- study switched motor neurons of FDL (FT) and soleus (ST)
- found that they both switched types

what happens to a slow twitch muscle when it is switched to fast twitch

causes damage

role of fibroblasts in muscle repair

- express ECM components (mostly collagen) to form new basement membrane and endomysium
- helps to guide motor neuron to newly formed fibres

why is the balance bw myoblasts and fibroblasts important (when can this balance be lost)

need the appropriate amount of contractile components to structural
- diseases impact the balance

signal for fibroblasts

- stress on connective tissue

what does diabetes do to the balance of fibroblasts and myoblasts what does this cause

- muscle damage leads to overabundance of collagen (fibroblasts activity)
- too much ECM allows for adipocytes (fat droplets) to develop where muscle should be

what processes regulate muscle mass --\> what do they effect

- hormones
- time under tension
- availability of amino acids
- alpha motor neurons

--\> affect ability to repair damage, regulation of protein synthesis, regulation of gene transcription

what is net protein turnover --\> is it better to increase synthesis or decrease breakdown

the balance bw protein synthesis and proteolysis
--\> better to increase synthesis than decrease breakdown

what increases protein synthesis

- exercise and food (protein intake) stimulate protein synthesis and limit proteolysis

describe 12 hours of protein synthesis and breakdown

- synthesis is cyclical
- eating raises synthesis, exercise raises degradation
- with no training there is a more dramatic cycle of synthesis and degradation
- training can cause more protein to be made and less to be broken down
- less dramatic cycle with training and adequate PRO intake

time course for protein synthesis and gene signalling responses after exercise

- specific genes turn on immediately following exercise
- immediately there is a steady increase in protein synthesis that lasts for up to four days
- CROSS HALFWAY THRU THE 1 DAY POINT
- RNA peaks in an hour post PRO accumulates much later

where does the RNA come from to translate new proteins

basal levels in the cell, existing pool

how are genes activated by exercise

- translation of PS turned on quickly after exercise
- ribosomes activated which are responsible for translation
- transcription of genes associated with exercise are turned on and muscle specific

how does chronic exercise change the genes

causes repeated increases in expression of related genes which mediates the long term adaptation

how many genes are activated by exercise

thousands (includes actin and myosin related genes)
- aerobic exercise activates different ones than RT

time course of signalling

increases immediately to highest amount (more than mRNA, and accumulation)

how to increase muscle mass and what contributes to this pathway

- must be coordinated
- intracellular signalling pathways contribute to this

turn on protein synthesis machinery (ribosomes) --\> translate mRNA to protein --\> express more of the correct genes --\> reduce/limit proteolysis

how does cell signalling effect the structure of the cells

some proteins need to be more stimulated so pathways have to move, there is a change in the environment, and change in metabolites

what does high amounts of AMP suggest and why

- sign that the muscle is in a low energy state
- AMP accumulates with increased ADP which accumulates when ATP is hydrolyzed

what senses the levels of AMP and how does it change with training

AMPk (kinase) sense and stimulates transcriptional factors that lead to mitochondrial increase to prevent AMP accumulation by increasing ATP formation

protein associated with aerobic exercise vs RT

PGC-1 alpha: aerobic
mTOR: RT

how does resistance training lead to protein synthesis

RT causes increased muscle tension, nerve activity, damage, and hormone release that signal the muscle --\> signals turning on expression of appropriate genes and increases rate of protein synthesis

how is mTOR turned on by RT

Akt activates due to insulin and signals the activation of mTOR which then targets over 800 proteins, 3 leading to increased ribosome activity --\> protein synthesis

how does AT inhibit mTOR

AT signals AMPK which inhibits mTOR

how is AMPK stimulated and then what does it do

AMP accumulates as a result of exhaustion of the muscle --\> AMPK senses this and is activated --\> stims glucose uptake, FA oxidation, inhibits mTOR, and initiates genes that create mitochondria --\> increase PGC-1 alpha --\> turns on mitochondrial genes

how does training effect signalling pathways

determines what genes are turned on and what is made (mTOR vs PGC-1 alpha)

function of myostatin - what happens if it does not exist in cows and humans

represses muscle growth
- without it we get super muscular cows
- super muscular babies, concern for the heart

what does the knockout of myostatin cause not in skeletal muscle

- vasoconstriction in vessels and enlarged heart

what happens to myostatin when muscle growth occurs and when is it elevated

- myostatin dips down with growth, but ensures there is not overgrowth
- it is elevated during periods of muscle disuse, muscle wasting diseases and other chronic diseases
- expression temporarily reduced after acute exercise

what effects does myostatin exert on skeletal muscle

- blocks Akt/mTOR signalling and opposes insulin
- inhibits protein synthesis and up regulates proteolysis
- suppresses satellite cell proliferation and differentiation

what is T1D

autoimmune disease resulting in the destruction of insulin producing beta cells in the pancreas which leads to hyperglycemia
- 10x increased risk of CVD

intensive vs conventional insulin treatment

intensive - monitor throughout the day and adjust levels (strategy most widely used)
conventional - one dose of insulin the the morning

what does the intensive treatment of T1D cause when coupled with exercise

hypoglycemia

what is HbA1c

percent of glycated hemoglobin (blood sugar levels)