Transcript Limits of Human Performance

Amino acid metabolism
proteins
• Only foodstuff that can
form structures (tissues
and enzymes)
• Made up of amino acids
• Protein synthesis,
enzyme formation
• Can serve as fuel during
long-term work
• 0.8 g/kg recommended
for adults; probably too
low for athletes
Protein structure: Amino acids
• Essential vs
non-essential
– Essential:
NOT made
by body
– Nonessential:
made by the
body
Protein structure
• Carboxyl and
amino termini come
together to from
protein structures
(peptides)
Amino
acid
Proteins in the diet
• Digested in stomach
and small intestine
– Hydrocholoric acid
(stomach)
– Trypsin,
chymotrypsin,
carboxypeptidase
(from pancreas)
– Polypeptidases and
dipeptidases in
intestinal cells finish
digestion
• The amino acid pool
– Free amino acids in the liver, skeletal muscle, plasma, interstitial
fluid and intracellular water
– All interconnected in that metabolism in one affects the others
– Continuous excretion of nitrogenous end-products
– Necessitates constant input of new amino acids
– So, CONSTANT Protein turnover
Nitrogen balance
• Nitrogen is a
component of AAs
– Thus, used as a
marker of protein
metabolism
• Protein intake
necessary to balance
nitrogen turnover
(input vs excretion)
– 0.8-1.0 g/kg is
sufficient for most
– 1.2-1.6 g/kg is the
highest
recommendation for
athletes
Removal of nitrogen
• Before amino
acids can be used
as fuel, nitrogen
group must be
removed
• Two ways
– Deamination
– Transamination
• Glutamate is a
key player in both
Removal of Nitrogen
• Deamination
– Occurs in liver
1) Requires NAD+ as
oxidizing agent
2) Produces
ammonium ion
3) α-ketoglutarate can
be used in Kreb’s
cycle
• Called anaplerotic (to
fill) addition to Kreb’s
cycle
1
2
3
Removal of Nitrogen
• Transamination
– Much more
common
– Transfers amine
group from amino
acid to keto acid
Keto
acid
AA
• SGPT and SGOT
transaminases in
liver
Keto
acid
AA
Excretion of nitrogenous wastes
2
• Ammonia (small amt)
• Most is excreted as urea
• Urea cycle
1) Formation of carbamoyl
phosphate from ammonia
and Co2
2) Addition of aspartate
3) Production of fumarate
(Kreb’s cycle intermediate)
4) Produces Urea
1
4
3
Gluconeogenic amino
acids
1
• Some amino acids used
for gluconeogenesis
1)Pyruvate to OOA
2)OOA to PEP
3)PEP begins “reverse
glycolysis” or
gluconeogenesis
• So, amino acids that
give rise to pyruvate and
oxaloacetate
– Can form
phosphoenolpyruvate
– Can be converted to
glucose
2
Anaplerotic and cataplerotic reactions
• Anaplerotic (adding to)
• Cataplerotic (emptying)
– These Rx add to or
deplete the Kreb’s cycle
• Glutamate-glutamine
• Key intraorgan
nitrogen transport
vehicle, fuel source
for GI tract and
immune system and
gluconeogenic
precursor
Branched chain amino acids
• Leucine, Isoleucine
and valine (LIV)
• Catabolized mostly
in skeletal muscle
• Leucine:
– Forms acetyl-CoA,
acetoacetate and
glutamate
• Leucine is thus
called ketogenic
Transamination
AA metabolism
• AA can be used in the following ways
– Structural (proteins)
– Anaplerotic additions to Kreb’s cycle
• This keeps the Kreb’s cycle working
– Oxidized directly
• Branched chain AA
– Other contributions to energetics
• Ketogenic
– Produce ketone bodies when broken down
• Glucogenic
– Contributes to gluconeogenesis
Glucose-alanine cycle
• Used during
fasting
• Alanine can
come from
glycolysis or AA
metabolism
– Glycolysis
• Kreb’s cycle
backs up during
starvation
– Pyruvate
transaminated to
alanine
– Alanine
converted to
glucose in liver
Glucosealanine II
• Other amino acids
can also form
alanine (glucogenic
AA, anything that
gives rise to
pyruvate or OOA)
• So when Pyruvate
builds up, converted
to Alanine (1)
• Alanine shuttled
to liver
– Converted to
glucose
1
Effects of endurance training on AA
metab
• Greater rates of
AA metabolism in
trained subjects
– Greater oxidation
in human
subjects during
exercise
AA metabolism
• Note that leucine
oxidation
increases during
exercise
– This increases is
linear with respect
to exercise
intensity
– Particularly true in
fasted state
AA metabolism
1
• Note that alanine
appearance
increases during
exercise (1) and
this can come
from AA leucine
(2)
• Also, glucose
infusion reduces
AA oxidation (3)
2
3
AA metabolism
• However, exercise training does not appear to increase
AA metabolism in human subjects
– If anything, it is reduced
Ammonia scavenging during
high intensity exercise
• During high intensity
exercise, AMP is formed
– Adenylate kinase Rx
• ADP + ADP
ATP + AMP
• AMP then inhibits AK Rx
if it builds up
• AMP deaminated to IMP
• Muscle releases ammonia
(NH4+) during contraction
– Contains nitrogen
• Purine nucleotide cycle
Ammonia
scavenging
• Formation of
glutamine (1)
helps to transport
ammonia in blood
– Ammonia is toxic
– Transamination
• Glutamine goes
to kidney (2)
• Urea (3) and
glucose formed
(4)
4
2
3
1
Neuro-endocrine control of
blood glucose
Hormones
• Chemical messengers
– Produced and stored in a gland
– Secreted into the blood
– General and specific effects
• Two basic types
– Steroid
• Produced from cholesterol by adrenal cortex and gonads
– Polypeptides
• Amino acids
Hormones
• Powerful effects
• Precisely regulated
– Feedback control
(negative feedback)
• Mechanisms of action
– Affect cell permeability
(insulin)
– Activate an enzyme
(epinephrine)
– Protein synthesis (GH)
Blood glucose homeostasis
• When fed
– Liver
glycogenolysis
• When fasted
– Gluconeogenesis
• SNS helps in this
– Epi stimulates liver
glycogenolysis and
gluconeogenesis
• Hormones
– Released into blood
– Epinephrine and
nor-epinephrine
Hepatic glucose production during
exercise
• Maintenance of blood
glucose levels is
paramount
– Fuel source
– Anaplerotic additions to
Kreb’s
– Allows fat metabolism
– Needed by brain and
CNS
• Hormones that help
maintain blood
glucose
– glucoregulatory
Glucose homeostasis
• How difficult is this?
• Normal adult
– Blood volume = 5L
– Blood glucose = 100 mg/dl (1 g/L)
– 5g or 20 kcals (4kcal/g) worth of energy
– Only enough to support 1 min of maximal
activity!
• This means
– We must get plenty of CHO prior to and even
during activity
– Liver supplements this
Glucose homeostasis
• Glucose
production
increased in 2
ways
– Increased
absorption from
gut and liver
output
• Liver
glycogenlosis
• Liver
gluconeogenesis
Glucose homeostasis
• Note how addition of
arm exercise
increases
catecholamine levels
– glucoregulatory
hormone (raises blood
glucose)
• Insulin falls
– Decreases blood
glucose
• Thus hormonal
changes help maintain
blood glucose levels
Why increased?
Catecholamines and blood glucose
• Epinephrine and norepinephrine
• Epi binds to β-receptor
– Activates adenylate cyclase
– Muscle contraction increases
intracellular Ca2+ and Pi
• Stimulates glycogenolysis
– Muscle and liver
– Supports liver glucose
production
– Also increases lipolytic rate
Cyclic AMP
• Made from ATP (1)
• Intracellular messenger
• Activates many
processes in
metabolism
• Example
– Glycogenolysis
• Epinephrine binds to
receptor (2)
• Adenyl-cyclase creates
cAMP (3)
• cAMP activates
phosphorylase
EPI
1
2
3
Insulin and glucagon
• Insulin
– β cells of the islets of langerhans of pancreas
• Glucagon
– α cells
• Along with epinephrine and nor-epinephrine, main
hormones of glucose homeostasis
Insulin response to
exercise
• Falls in
response to
exercise
– Epinephrine
suppresses
insulin
secretion
• Thus
– Glucose
production is
increased
Why insulin?
• Insulin
– Helps facilitate
glucose transport
across sarcolemma
during rest
– Uses glucose
transporters (GLUT)
– GLUT-4
• Insulin mobilizes
transporters from
intracellular pool
• Transporters move to
sarcolemma
Glucose transport: exercise
• Muscular
contraction
– “insulin-like” effect
– GLUT-4 can
translocate due to
insulin or Ca2+
• So, muscular
contractions
– Cause release of
Ca2+
– This causes
translocation of Glut4 receptors
– Important as
epinephrine
(released during
exercise) inhibits
insulin
insulin
Neuro-endocrine control of
hepatic glucose production
• Gluconeogenesis
– Liver and kidneys
• 3 different enzymes
than glycolysis
– Pyruvate carboxylase
– PEP carboxylase
– Fructose 1,6
biphosphatase
• Glucose 6phosphatase
– Liver only
• So, muscle
resynthesizes glycogen,
liver and kidneys,
glucose
Pyruvate
kinase
Gluconeogenesis
• Those 4 enzymes are either nonexistent or
in small supply in skeletal muscle
• Found in large amts in liver and kidneys
• Pyruvate kinase (last step of glycolysis):
– virtually irreversible in skeletal muscle
– In liver, can be inhibited by cAMP and
phosphorylation (Ca2+-dependent protein
kinase)
– Reduces glycogenloysis and promotes
gluconeogenesis
Gluconeogenesis
• Pyruvate coverted to
oxaloacetate (A)
E
– High acetyl-CoA, low ADP
• Oxaloacetate converted to
Phosphoenolpyruvate (B)
D
– Low ADP
• Phosphoenolpyruvate
converted to Fructose 1, 6
bisphosphate (C)
• F 1,6 bisphosphate
converted to F6P (D)
– High citrate, low AMP
• Converted to glucose
(E)
C
B
A
Hepatic glucose production
The following hormones increase gluconeogenesis
• Inhibit pyruvate kinase
– Glucagon
– Epinephrine
– Nor-epinephrine
• Insulin
– Inhibits gluconeogenesis
Can muscle
make glucose?
• Glycolytic muscle can
produce glycogen from
lactate
– Glyconeogenesis
• Likely occurs early in
recovery
• Muscle lacks G6
phosphatase
– So can’t release glucose from
cell
• However, it is possible that
debranching enzyme can
release glucose from
glycogen
– May help explain very rapid inc
in blood glucose (fig 9-13)