Heart Flashcards
1
Q
liver adapts to changing metabolic condition
A
- portal vein carries nutrients to the liver
- hepatocytes turn nutrients into fuel
- hepatocyte enzymes turn over quickly
- enzymes increase or decrease with changes in diet and the needs of other tissues
2
Q
fates for glucose-6-phosphate in the liver
A
- dephosphorylate to yield free glucose to send to other tissues
- make into liver glycogen
- enter glycolysis, make acetyl CoA and then ATP for hepatocytes themselves
- enter glycolysis, make acetyl CoA to be made into fatty acids and then TAGs
- enter pentose phosphate pathway to yield NADPH and ribose-5-phospahte
- glycogen -> G1P -> G6P -> glucose -> glycolysis -> acetyl CoA -> energy or fatty acids -> TAG
3
Q
muscles (myocytes): two types
A
- slow-twitch (red muscle):
- fed by many blood vessels
- rich in mitochondria (to provide energy via slow and steady oxphos)
- fast twitch (white muscle):
- fewer mitochondria and lower O2 delivery
- uses ATP faster and fatigues faster due to greater demands (more tension) combined with reduced O2 delivery
- endurance training can increase mitochondria
4
Q
energy source for muscle contraction
A
- muscle glycogen -> glucose-6-phosphate
- yields 3 ATP, not 2 (as in glycolysis)
- glycogen breakdown skips ATP dependent hexokinase rxn
- pyruvate -> lactate to create NAD+ to enable glycolysis to continue
- phosphocreatine is another energy source
- phosphocreatine + ADP -> burst of heavy activity -> creatine + ATP (other way around during rest)
- acted on by creatine kinase to release ATP
- during light activity or rest- fatty acids, ketone bodies, blood glucose is used
5
Q
hormonal control of glycogen mobilization
A
- epinephrine cascade stimulates glycogen phosphorylase
- break down glycogen in muscle and liver
6
Q
O2 debt
A
- after vigorous exercise, rapid breathing continues
- used for oxidative phosphorylation to build proton gradient and replenish ATP
- ATP used for gluconeogenesis to use up lactate and restore muscle glycogen concentration (cori cycle)
7
Q
the cori cycle
A
- in skeletal muscle that is capable of bursts of activity there is a process that allows the muscle to receive ATP from aerobic mitochondria or anaerobic catabolism that only uses glycolytic path
- during anaerobic activity lactate is produced
- lactate enters the blood and goes to the liver -> uses lactate as a fuel
- uses ATP in gluconeogenesis to make glucose form lactate (during recovery)
- glucose leaves liver and returns to the muscle which uses its own glycogenic pathway to build up glycogen for next period of active contraction
- liver making glucose from lactate
- muscle making lactate from glucose
- there is a version of the cori cycle that works in the heart
8
Q
heart muscle versus skeletal muscle
A
- heart muscle has more mitochondria (50% of cell volume)
- it is fueled primarily by fatty acids (some ketones, some glucose, some phosphocreatine)
- uses fatty acids (preferably) as the krebs cycle substrate
- glycolytic path runs through pyruvate and goes through part of gluconeogenesis to make oxaloacetate and malate -> these are kreb cycle intermediates that can now use the krebs cycle to oxidize acetyl CoA (from fatty acids) all the way to CO2
- it is an aerobic organ
- if the O2 supply is cut off, the muscle dies -> myocardial infarction
9
Q
aerobic organ
A
- makes ATP in mitochondria
- substrate of choice will be fatty acid oxidation
- acetyl CoA is the substrate of the krebs (doesnt prefer)
- acetyl CoA is used for oxidation not used for biosynthetic purposes
10
Q
heart: energy
A
- three major demands: house keeping functions (you need ATP), ion pumping for contraction, contraction (ATP for movement of myosin heads)
- energy demands are a lot
- we must integrate fatty acid catabolism and carbohydrate catabolism to get the energy we need
- getting fatty acids into the mitochondria is the rate limiting step in fatty acid catabolism
- carnitine acyl transferase shuttles the fatty acids into the heart
- once the fatty acids are in they will be catabolized/oxidized all the way to acetyl CoA -> no intramitochondrial regulatory step (this is why regulation at the carnitine acyl transferase is important)
- carbohydrates are converted via the glycolytic pathway to pyruvate
- pyruvate can be completely oxidized to acetyl CoA via pyruvate dehydrogenase however if there is enough acetyl CoA from fatty acid catabolism it can chose not to
11
Q
heart: acetyl CoA
A
- derived from fatty acid catabolism or carbohydrates converted from pyruvate to acetyl CoA via pyruvate dehydrogenase
- fatty acid oxidation mostly is unregulated
- fatty acids is the preferred method of making acetyl CoA
- acyl transferase that make use of carnitine bring fatty acids into the heart -> regulated
- use a little bit of gluconeogenic pathway to make kreb cycle intermediates in order to make full use of the fatty acid derived acetyl CoA
- acetyl CoA inhibits pyruvate dehydrogenase -> fatty acid catabolism shuts down carbohydrate metabolism
- krebs cycle and ETC of mitochondria is supplying the ATP
12
Q
creatine
A
- if there is more than enough ATP the heart stores glucose and uses it to make glycogen
- BUT more importantly it can store creatine
- creatine can be phosphorylated to phosphocreatine
- phosphocreatine has a high energy phosphate bond -> high energy nitrogen bond that can be used to make ATP
- phosphocreatine is hydrolyzed and phosphorylates ADP
13
Q
advantage of acetyl CoA from fatty acid catabolism/oxidation: 2 inhibition methods
A
- two products of fatty acid oxidation that we need to consider: coenzyme A in the form of acetyl CoA and NADH
- both of these products are regulatory towards pyruvate dehydrogenase -> allosteric negative effectors
- fatty acid oxidation inhibits the oxidation of pyruvate via pyruvate dehydrogenase to acetyl CoA
- shut down is not extreme bc the activity of the mitochondria is enough to use up a lot of the NADH in ETC and acetyl CoA in the krebs which slows inhibition
- if krebs and ETC slow down the allosteric negative effectors accumulate and feedback on to pyruvate dehydrogenase
- NADH and acetyl CoA can shut down pyruvate kinase through another mechanism (analogous to shut down of PFK2 and F26biP
- a kinase stimulated by cAMP phosphorylates E1 of pyruvate dehydorgenase -> inhibits
- phosphatase stimulated by insulin removes the phosphate from E1 -> relieves inhibition
- excess NADH also tends to slow the glycolytic pathway at other steps (glyceraldehyde-3-phosphate dehydrogenase step) -> shys away from glycolysis while fatty acid catabolism is going on
14
Q
heart: lactate
A
- heart takes up lactate from skeletal muscle
- extracts lactate from the blood and use it for fuel
- relies heavily on lactate generated by anaerobic glycolysis in skeletal muscle and extracted from the blood as a major energy source
15
Q
depletion of O2 to the heart
A
- when we decrease blood and therefore O2 we decrease mitchondrial metabolism which is necessary for fatty acid catabolism -> glycolysis increases which causes accumulation of lactate, protons (lower pH)
- atherosclerotic cardiovascular disease
- blood passes through at a reduced rate (reduced prefusion) -> low O2 and nutrients
- reduced reduction of blood and O2 will compromise hearts ability to wash out metabolic products of contractile activity
- the heart may switch over to some modest anaerobic glycolysis -> uses glycogen stores to supplement reduced glucose form reduced blood flow -> generates lactate
- accumulation of lactate
- protons form glycolysis and mitochondrial metabolism will decrease pH -> negative effect on glycolysis (PFK is pH sensitive)
- if you lower pH the muscle cant carry out glycolytic metabolism as well
- therefore is glycolysis if slowed, and mitochondrial activity is slowed (low oxygen) -> myocardial infarction
- clots will cause serious problems
16
Q
chronic ischemia
A
- people who blood supply is not completely cut off
- function normally by reducing the obligate dependency of the heart on fatty acid catabolism
- partially inhibit the catabolic pathway
- do this by using trimetazidine- partial inhibitor
- trimetazidine inhibits thiolase enzyme (beta-ketoaceyl transferase)
- trimetazidine is a partial inhibitor meaning that fatty acid catabolism is not completely stopped but significantly reduced
- partially reduction of fatty acid catabolism -> NADH and acetyl CoA (products) is partially depleted -> pyruvate dehydrogenase is less inhibited
- heart switches from fatty acid catabolism to glycolytic oxidation (pyruvate dehydrogenase) when under chronic ischemia (slow blood flow)
- glucose and lactate are used as sources of energy (they are not absolutely dependent on O2) -> can use anaerobic when there is less O2
17
Q
diabetes
A
- ketone bodies accumulate in blood (ketosis)
- at risk for elevated levels of acetyl CoA and NADH in the cardiac mitochondria
- endogenously produced acetyl CoA and NADH from fatty acid oxidation combine with the other acetyl CoA NADH cardiac mitochondria -> reduce the ability of the heart to use glycolysis (inhibits pyruvate dehydrogenase)
- ketone bodies are sources of acetyl CoA
- only organ that can make ketone bodies, but also cant use -> liver
- heart can use ketone bodies -> accumulation of acetyl CoA -> poorly perfused (same as chronic ischemia)
18
Q
maintaining angina (chest pain) due to cardiac ischemia
A
- give insulin -> helps allow entry of glucose into cardiac muscle
- insulin also relieves the inhibition of pyruvate dehydrogenase E1 through phosphatase
- improving blood flood -> nitroglycerin (dilates vessels)
- inhibit fatty acid oxidation with drugs like trimetazidine
19
Q
chloroacetate
A
- specific inhibitor of the kinase that inhibits E1 by being phosphorylated
- drug
20
Q
drugs that inhibit the carnitine acyl transferases
A
- reduces the levels of fatty acids entering the heart
- allow the heart to rely more on glycolysis and carbohydrate metabolism
21
Q
resting state
A
-flux through krebs is low bc there is low local concentrations of NAD+ if the rate of oxidative phosphorylation is low
22
Q
cardiac muscle
A
-benefits from a good O2 supply for mitochondrial function but then uses the glycolytic pathway for synthesis of krebs cycle intermediates rather than acetyl-CoA while fatty acids are preferentially catabolized
