Download 2 Lec 4 Muscle Metabolism V10

Chapter 9 & 24
Muscle
Metabolism
© Annie Leibovitz/Contact Press Images
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Introduction: Muscle Metabolism – Energy for
Contraction
• Energy is never created nor destroyed, only
stored or released
• Bonds = energy – ATP is the currency for
cellular energy
• Energy is stored in the bonds.
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9.6 Energy for Contraction and ATP
Providing Energy for Contraction
• ATP supplies the energy needed for the muscle
fiber to:
– Move and detach cross bridges
– Pump calcium back into SR
– Pump Na+ out of and K+ back into cell after
excitation-contraction coupling
• Available stores of ATP depleted in 4–6 seconds
• ATP is the only source of energy for contractile
activities; therefore it must be regenerated quickly
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Providing Energy for Contraction
• ATP is regenerated quickly by three
mechanisms:
– Direct phosphorylation of ADP by creatine
phosphate (CP)
– Anaerobic pathway: glycolysis and lactic acid
formation
– Aerobic respiration
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Figure 9.16a Pathways
for
regenerating
ATP
Direct phosphorylation
during muscle activity.
Coupled reaction of creatine
phosphate (CP) and ADP
Energy source: CP
CP
ADP
Creatine
kinase
Creatine
ATP
Oxygen use: None
Products: 1 ATP per CP, creatine
Duration of energy provided:
15 seconds
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Figure 9.16b Pathways
for
regenerating
ATP
Anaerobic pathway
during muscle activity.
Glycolysis and lactic acid formation
Energy source: glucose
Glucose (from
glycogen breakdown or
delivered from blood)
Glycolysis
in cytosol
2
O2
ATP
net gain
Released
to blood
Pyruvic acid
O2
Lactic acid
Oxygen use: None
Products: 2 ATP per glucose, lactic acid
Duration of energy provided: 30–40
seconds, or slightly more
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Providing Energy for Contraction (cont.)
• Anaerobic pathway: glycolysis and lactic
acid formation (cont.)
– Lactic acid
• Diffuses into bloodstream
• Used as fuel by liver, kidneys, and heart
• Converted back into pyruvic acid or glucose by liver
– Anaerobic respiration yields only 5% as much
ATP as aerobic respiration, but produces ATP
2½ times faster
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Anaerobic Glycolysis
• Fast pathway, but does not produce much
ATP
• Important for the first 30 – 40 sec. of
strenuous activity if enzymes and fuel are
available
• Stored ATP, CP and glycolysis can support
strenuous muscle activity for 60 sec.
• At full speed lactic acid accumulates,
lowering pH which halts reaction
• At full speed, glucose might not be supplied
fast enough
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Providing Energy for Contraction (cont.)
• Aerobic respiration
– Produces 95% of ATP during rest and light-tomoderate exercise
• Slower than anaerobic pathway
– Consists of series of chemical reactions that
occur in mitochondria and require oxygen
• Breaks glucose into CO2, H2O, and large amount ATP
(32 can be produced)
– Fuels used include glucose from glycogen stored
in muscle fiber, then bloodborne glucose, and
free fatty acids
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• Fatty acids are main fuel after 30 minutes of exercise9
Figure 9.16c Pathways
for
regenerating
ATP
Aerobic pathway
during muscle activity.
Aerobic cellular respiration
Energy source: glucose; pyruvic acid;
free fatty acids from adipose tissue;
amino acids from protein catabolism
Glucose (from
glycogen breakdown or
delivered from blood)
O2
Pyruvic acid
Fatty
acids
O2
Aerobic respiration
in mitochondria
Amino
acids
32
CO2
H2O
ATP
net gain per
glucose
Oxygen use: Required
Products: 32 ATP per glucose, CO2, H2O
Duration of energy provided: Hours
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Oxidation of Glucose (cont.)
• Citric acid cycle
– Also called Krebs cycle
– Occurs in mitochondrial matrix
– Fueled by pyruvic acid from glucose breakdown
and fatty acids from fat breakdown
• Prep. Step - Pyruvic acid is converted to acetyl
CoA
• Requires oxygen, but does not directly use it
• Preferred method of ATP production
• During rest/light exercise AR yields 95% of ATP
needed
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Oxidation of Glucose (cont.)
• Citric acid cycle (cont.)
• Transitional phase is where each pyruvic acid
is converted to acetyl coenzyme A (acetyl
CoA) in three steps
• Each acetic acid is decarboxylated and
oxidized, generating:
– 3 NADH + H+
– 1 FADH2
– 2 CO2
– 1 ATP
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Figure 24.7 Simplified version of
the citric acid (Krebs) cycle.
Glycolysis
Citric
acid
cycle
Electron
transport chain
and oxidative
phosphorylation
Carbon atom
Pi
Inorganic phosphate
CoA Coenzyme A
ATP
ATP
ATP
Cytosol
Mitochondrion
(matrix)
Pyruvic acid from glycolysis
NAD+
CO2
Transitional
phase
NADH + H+
CoA
Acetyl CoA
Oxaloacetic acid
(pickup molecule)
NADH + H+
Citric acid
(initial reactant)
CoA
NAD+
Isocitric acid
Malic acid
NAD+
Citric acid
cycle
CO2
NADH + H+
a-Ketoglutaric acid
Fumaric acid
CoA
CO2
FADH2
Succinic acid
FAD
CoA
GTP
ADP
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Succinyl-CoA
GDP +
NAD+
NADH + H+
Pi
ATP
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Summary of ATP Production
– Complete oxidation of 1 glucose molecule
– Totals between substrate-level phosphorylation
and oxidative phosphorylation equal 32 ATPs
• Glycolysis + Krebs cycle + electron transport chain
– But….energy is required to move NADH + H+
generated in glycolysis into mitochondria, which
uses up ~2 ATPs, so final total is 30 ATPs
produced
• There is still uncertainty on final total
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Figure 24.11 Energy yield during
cellular respiration.
Electron
shuttle across
mitochondrial
membrane
Glycolysis
Glucose
Mitochondrion
2 NADH + H+
Cytosol
Pyruvic
acid
2 NADH + H+
2
Acetyl
CoA
6 NADH + H+
Citric
acid
cycle
2 FADH2
Electron transport
chain and oxidative
phosphorylation
(4 ATP – 2 ATP
used for
activation
energy)
Net +2 ATP
by substrate-level
phosphorylation
10 NADH + H+  2.5 ATP
2 FADH2  1.5 ATP
+2 ATP
by substrate-level
phosphorylation
+ about 28 ATP
by oxidative
phosphorylation
–2 ATP (average shuttle cost)
About
30 ATP
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Typical
ATP yield
per glucose
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Providing Energy for Contraction (cont.)
• Energy systems used during sports
– Aerobic endurance
• Length of time muscle contracts using aerobic
pathways
– Light-to-moderate activity, which can continue for hours
– Anaerobic threshold
• Point at which muscle metabolism converts to
anaerobic pathway
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Figure 9.17 Comparison of energy sources used
during short-duration exercise and prolongedduration exercise.
Short-duration, high-intensity exercise
6 seconds
10 seconds
ATP stored in
muscles is
used first.
ATP is formed
from creatine
phosphate and
ADP (direct
phosphorylation).
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30–40 seconds
End of exercise
Glycogen stored in muscles is broken down to
glucose, which is oxidized to generate ATP
(anaerobic pathway).
Prolonged-duration
exercise
Hours
ATP is generated by
breakdown of several nutrient
energy fuels by aerobic
pathway.
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Muscle Fatigue
• Physiological inability to contract despite
continued stimulation
• Usually occurs when there are ionic imbalances
– Levels of K+, Ca2+, Pi can interfere with E-C
coupling
– Prolonged exercise may also damage SR and
interferes with Ca2+ regulation and release
• Lack of ATP is rarely a reason for fatigue,
except in severely stressed muscles
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Excess Postexercise Oxygen Consumption
• For a muscle to return to its pre-exercise state:
– Oxygen reserves are replenished
– Lactic acid is reconverted to pyruvic acid
– Glycogen stores are replaced
– ATP and creatine phosphate reserves are
resynthesized
• All replenishing steps require extra oxygen, so
this is referred to as excess postexercise
oxygen consumption (EPOC)
– Formerly referred to as “oxygen debt”
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Heat Production During Muscle Activity
• ~40% of energy released in muscle activity
useful as work
• Remaining energy (60%) given off as heat
• Dangerous heat levels prevented by radiation of
heat from skin and sweating
• Shivering - result of muscle contractions to
generate heat when cold
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Skeletal Muscle Cramps
Cause
• Insufficient blood flow or oxygen = anaerobic ATP
production
• Lactic acid accumulates and causes muscle irritation
• Due to dehydration and insufficient K+ , Ca 2+ and rarely
Na+
Prevention
• Hydration, fitness and adequate diet
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Muscular Dystrophy
• Duchenne muscular dystrophy (DMD):
– Most common and severe type
– Inherited, sex-linked, carried by females and
expressed in males (1/3500) as lack of
dystrophin
• Cytoplasmic protein that stabilizes sarcolemma
• Fragile sarcolemma tears  Ca2+ entry  damaged
contractile fibers  inflammatory cells  muscle
mass drops
– Victims become clumsy and fall frequently;
usually die of respiratory failure in 20s
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Muscular Dystrophy
– No cure
– Prednisone improves muscle strength and
function
– Myoblast transfer therapy disappointing
– Coaxing dystrophic muscles to produce more
utrophin (protein similar to dystrophin) successful
in mice
– Viral gene therapy and infusion of stem cells with
correct dystrophin genes show promise
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