The Problem

Energy Supplies and • Muscle avidly consumes ATP using

Control of Muscle actomyosin ATPase and Ca2+ pump
ATPase
Metabolism • On activation
activation, muscle metabolic rate
increases more than 100-fold
• If ATP were depleted muscle would go into
BL0224 Physiological Control rigour (rigor mortis)

KCL ICHS ©2008

1 2

The Solution External Supplies

Fatty
• Have a range of mechanisms for supplying Glucose
acids
ATP according to needs of speed and
endurance
muscle
• Store lots of energy within each muscle
cell ADP + Pi ► ATP

• Make sure that a range of fatigue

Lactate O2
mechanisms exist!

CO2
3 4

Internal Supplies Internal Pathways

Lipid Lipid
Glycogen
Glycogen Droplets Droplets
(2%) (1%)
Creatine phosphate
Creatine phosphate
(7% osmotic volume)

Glycolysis Lohmann Lipolysis

ATP
mitochondria
ATP
lactate pyruvate mitochondria

anaerobic aerobic
5 6

1
 Oxygen Uptake Kinetics Limiting Timescales of Fuel Sources

Trained subject not only Anaerobic

has larger VO2 max but
the uptake occurs much
trained
faster, 26sec time
constant c.f. 45sec in Aerobic
untrained subject.

Caputo. Eur J Appl Physiol 93 87

(2004)

Aerobic metabolism
takes up to 1 min to
fully activate – thus
brief exercise must be
supported by
anaerobic metabolism This diagram is realistic only for maximal exercise resulting in
7 fatigue at the time plotted. 8
Exercise Physiology, Robergs & Roberts

Nuclear magnetic resonance of P

Phosphocreatine
• Lohmann reaction (creatine kinase) acts Pi
as a temporal buffer for ATP CrP
CrP ATP
• Acts as a pH buffer CrP
• Acts as a spatial buffer to move ~P from Pi
heavy
mitochondria to cross-bridge exercise
• Pi release stimulates glycolysis
moderate
• Regulated [ADP] drives Krebs cycle exercise
Pi
• High Pi induces fatigue
9
rest 10

The anaerobic reactions

Lohmann Reaction (1939)
ADP + CrP + H+ ATP + Cr
pH buffer (Lohmann) creatine kinase

• k = 100 so CrP acts as

a buffer for ATP
• ADP held low rising to
Fatigue?
0.2 mM in fatigue
[ADP] ~ [creatine]/500
• CrP acts as pH buffer
• CrP acts as spatial
buffer to move ATP
Net reaction of A + B from mitochondria to
myosin
i.e. from PCr ► Cr + Pi + energy
glycogen 11 12
Jones & Round

2
 Effects of Creatine Supplementation
The Phosphocreatine Shuttle
1: Faster Aerobic [ATP].[creatine]
[ADP] ~ creatine/500 [ADP].[PCr] =K
Recovery

2: Prolonged
Anaerobic
Endurance

3: Decreased Deamination
ATP movement 2 ADP ► ATP+ AMP
(myokinase; AMP►ammonia)
J F Clark (1997) J Athl Train 32: 45–51. Twenty grams per day of creatine can be added to the
13 Creatine and Phosphocreatine: A Review 14
Maughan & Gleeson
athlete's diet for 1 to 2 weeks and reduced to 5 g/day
of Their Use in Exercise and Sport for the remainder of the sports season.

Phosphocreatine Resynthesis Glycogen

• Glycogen content is 2% - 4% of muscle
31P NMR
in vivo human • Stores 100 - 200 mM hexose
Rarkevicius 1998
• Exhaustion correlates well with glycogen
Recovery
d l ti (this will lead to PCr depletion)
depletion
within 2 min
• Slow repletion
• Both depletion and high CHO diet lead to
Needs blood greater storage of glycogen
flow to
remove
lactate
15 16
Maughan & Gleeson

Basic Muscle Metabolism Phosphorylase

insulin noradrenaline
PCr use leads to
glycogen breakdown glucose fatty acids (glycogen breakdown)
Cr + Pi
cell
stimulated by:
Actomyosin
ATPase

phosphorylase glucose-6P
glycogen
PCr
• inorganic phosphate – from Lohman
3 ATP lipid
NAD+
mitochondria
• free calcium – from activation
NADH • noradrenaline via cAMP – prolonged
lactic acid pyruvate
exercise
mitochondria
acetyl coA
33 ATP KREBS
CYCLE CO172 18

3
 Glycogen Content Glycogen Recovery
during high intensity cycling is very slow

mM hexose

70

Fatigue
60

es at 70 min
50
40
30
20
10
0
Rest 1 hr +1 hr +2hr
exercise

19 Saltin 1999 JP 514 293 20

Maughan & Gleeson

Glycogen Recovery
following one-legged exhaustive exercise Diet, Glycogen & Endurance
High CHO
diets can
Exercise induces
double both
enhanced glycogen
glycogen
storage
storage and
duration to
exhaustion

Takes about a
day to recover!

Bergstrom 1966
21 22

Carbohydrate Loading
finally 3 day high CHO
• 1966 Bergstrom - supercompensation
3 day normal diet • 1967 Bergstrom – carbohydrate loading
then 3 day low CHO • 1969 Marathon won by Ron Hill using
d l ti th
depletion then lloading
di carbohydrate
b h d t di diett
• Current practice
Reduce training load and increase
carbohydrate for last few days – ‘pasta
parties’
23 24

4
Is Carbo-loading as Effective for Women as it is for Men?
Anaerobic Metabolism
Tarnopolsky et al (1995) – Men can increase muscle glycogen by 41%
(P<0.05) in a carbo-loading protocol whereas women did not increase and Lactate
muscle glycogen.
Tarnopolsky et al (2001) – Compare
• Prolonged high force contractions use fast
loading and exercise. HAB = habitual glycolytic fibres (IIb) where ATP use is faster
diet. than mitochondria can supply
• Raised NADH promotes formation of lactate
• Lactate transports out of cell and is used by
Tarnopolsky J Appl Physiol
cardiac muscle and other muscle cells
78:1360, 1995.
Tarnopolsky J Appl Physiol
• Provides only 3ATP per glycogen hexose and
91:225, 2001. costs 5 ATP to rebuild

25 26

Glycolytic Intermediates
G6P increases
Rate limiting

Rate-
limiting
step
Needs NAD+

Needs ADP
You don’t need to know
the individual steps!
Fig. 6-7 Accumulation of glycolytic intermediates during a fatiguing isometric contraction. A, concentrations of glycolytic
intermediates before and after the phosphofructokinase (PFK) reaction (arrow). B, accumulation of both a-glycerophosphate and
lactate, which are needed to regenerate NAD from NADH. gdw, grams dry weight; Gluc, glucose; G1P, glucose 1-phosphate; G6P,
glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6P, fructose 1,6-biphosphate; G3P, glyceraldehyde 3-phosphate; DHAP,
27 dihydroxyacetone phosphate; αGP, α-glycerophosphate; Lac, lactate. (Redrawn from the data of Edwards et al 1972.) 28

Glycolysis Products Lactate Removal

10 Rate Enhanced
• pyruvate 50% by active
lactate, mM

• ATP recovery at
• NADH ~30% VO2max
5 Active recovery, %VO2max
pyruvate + NADH ◄► lactate + NAD+
65%

0%
(Gibbs free energy, ΔG ~ 0) 7 min
35%
exercise
(lactate is a response to acid)
29 0 McArdle Fig. 7.1
30
0 15 Time, min 30

5
Lactate flux during exercise of Lactate Transporters in Slow and Fast Fibres

a glycogen-depleted leg Slow fibres have

lots of MCT1
lactate transporter
lactate absorbed
(km = 3.5 mM) so
by depleted leg saturates and acts
as H+ regulator or
for lactate uptake

lactate
Lactate exported by
non-depleted leg
Fast fibres have lots of
MCT4 lactate transporter
(km = 35 mM) so act to
export even high levels of
lactate from muscle
Saltin. J Physiol (1999), 514 293-302 Photomicrographs of immunofluorescence labeling of MCT1 (A, B) and MCT4 (C, D) in the EDL (extensor
31 32
digitorum longus muscle) and the SOL (soleus muscle). MCT1 and MCT4 are visualized with Cy3-conjugated
secondary antibody. For methods, see Bergersen et al. (2006). Scale bars=150 μm.

Bicycle ergometer at 55% max.

Schrauwen-Hinderling
Unfit person J Appl Physiol 95: 2328, 2003
first burns
Oxidative Metabolism glycogen

Slow onset of
• Traditional view of ‘the wall’ as glycogen lipolysis
depletion
• Slow build-up of fatty acid oxidation
Fit person
(noradenaline ↑, insulin ↓ ) rapidly
uses Glycogen
• Glucose entry by GLUT4 transporter which lipolysis Depletion
has high Km (5 mM) promoted by insulin and
inhibited by glucose-6P

Maughan & Gleeson

33 34

Lactate Plasma fatty acids Chronic activity strongly decreases

depressed in
trained person
enhanced in trained
person
glycolytic enzymes Mitochondrial enzymes
increase

Phosphofructokinase is rate-
limiting for glycolysis

weeks

35 36

6
 Plasma Noradrenaline
note slow rise acting as stimulant to metabolism, especially lipolysis
Lipid Metabolism
• During 60 min exercise there is a depression of
insulin levels and increased sympathetic drive
(giving inc. plasma FFA)
• A rate-limiting step is FFA entry to mitochondria
– promoted by carnitine (not effective as a drug)
• Production of acetyl CoA from FFA oxidation
inhibits pyruvate dehydrogenase (glycolysis)
• 42% energy loss in resynthesis of lipid
• Type I (slow) fibres / moderate exercise use
FFAs exercise

37 60 min bicycle ergometer; Saltin 1999 J Physiol 514 293 38

Growth Hormone Plasma Insulin

GH aids switch to lipolysis as well as tissue growth stimulant exercise induces an increased sensitivity to insulin,
allowing long-term depression of insulin

60 min bicycle ergometer; Saltin 1999 J Physiol 514 293 39 60 min bicycle ergometer; Saltin 1999 J Physiol 514 293 40

Basic Muscle Metabolism lipid is dominant fuel

Hormonal changes in insulin noradrenaline
exercise ↓ glucose use, at normal exercise rates
↑ fatty acid use glucose fatty acids
Cr + Pi
cell
Actomyosin
ATPase

phosphorylase glucose-6P
glycogen
PCr

3 ATP lipid
NAD+
mitochondria

NADH

lactic acid pyruvate

Lipid is preferred fuel mitochondria

as acetyl coA inhibits acetyl coA
pyruvate use KREBS
33 ATP CYCLE CO412 42

7
 Training increases lipid use Training decrease glycogen use

43 44

Energy Efficiency
• ATP ► work 55% (at maximum work efficiency)

• CHO ► ATP 50% (mainly mitochondrial loss)

Muscle Energetics
so overall muscle efficiency, work out / energy in, ~ 27%

• CHO ◄► lipid 58%

“ muscle is a machine for converting
food into work - and it tastes good
• CHO ◄► glycogen 60%
too”
so internal storage as lipid or glycogen adds ~40% to energy cost

45 46

Energy Cost Energetics of fast and slow twitch

muscles of the mouse
mls oxygen per metre
(on treadmill)
Slow muscle has
Force - more curved force-
velocity velocity diagram
diagram

distribution of speeds fast (EDL)

chosen by horse slow (soleus)

47 48
Barclay 1993, J Physiol 472 61

8
 Fenn Curves Mechanical Power Efficiency
energy output (measured as heat production) (enthalpic efficiency)
increases during shortening w / (h + w)
i.e. increased cross-bridge turnover

Slow fibres optimal

shortening at low speed / high Can fit these to cross-bridge
force
kinetics using Huxley 1957
heat production model:
Soleus EDL
Attachment, /s 34 175
Detachment, /s 9 44

slow muscle has low isometric metabolism Soleus is not only slower but its cross-
bridges detaches relatively slowly.

49 50

What is efficiency? What is energy?

Enthalpy (H) Gibbs Free Energy (G)
• work efficiency • change in energy • energy available for
force x distance / metabolic cost
content in a chemical doing external work
- mechanical power output c.f. ATP rate (~ 50%)
- or cc.f.
f glucose / oxygen use (~
( 25%) reaction • the non-free
non free part is
• liberated as heat (h) locked in internal
• load efficiency = ‘economy’ and/or work (w) shape changes,
force x time / metabolic cost ΔH = h + w entropy (S)
• ΔH = ΔG - TΔS
- isometric metabolic rate

51 52

Energy Cost of Metabolism Metabolic Recovery

Aerobic glycolysis • Oxygen deficit and debt
Aerobic metabolism, following a brief anaerobic contraction, is associated with recovery heat equal
in size to the initial heat. Thus about half the free energy content of glucose is captured as ATP.
Mitochondrial coupling of phosphate to oxygen, P/O = 2.6 c.f. textbook value of 3, implies about 33
• Alactic and lactic recovery and pH
moles ATP per hexose.
• Lactate metabolism
Cost of glycogen storage ~ 40%
The breakdown of glycogen to lactate provides only 3 moles of ATP (2 moles if glucose is used)
and results in the release of lactate to the bloodstream. Lactate is metabolised, mainly by the heart,
• Recovery from exhaustive exercise
other muscles and the liver, within the next 30-60 minutes. This slower aerobic metabolism of
lactate provides full recovery of energy (i.e. 33 ATP / hexose). However sustained anaerobic
activity is supported mainly by glycogenolysis and the reformation of glycogen requires 2 ATP per
hexose. Thus there is an oxygen debt which is more than the original metabolic load:
yield/debt = 3/(3+2) = 0.6 (40% loss) .

Cost of fatty acid storage ~ 40%

Yield/debt in using fatty acids for storage = 8.1/14 ATP per CH2 = 0.58 (42% loss).

ICHS 2008
53 54

9
 Deficit and recovery from light exercise Oxygen Debt
i.e. oxygen uptake after exercise
• Recovery of oxygen stores (myoglobin) is
fast and small
oxygen deficit • During moderate exercise there is a
“oxygen debt”
phasic oxygen deficit reflected as a larger
(1.5x) recovery oxygen debt
• Fast time course (30s half time) that
matches phosphocreatine resynthesis

McArdle Fig 7.9

55 56

Oxygen
Oxygen Deficit - CrP
(630.7 ml)

Debt

Elderly people walking at 1 mph

J Gerontology A58:M734-M739
Oxygen-Uptake (VO2) Kinetics and Functional
Mobility Performance in Impaired Older Adults
Neil B. Alexander (2003)

57 McArdle Fig. 7.4

58

Heavy exercise & lactate Deficit and recovery from heavy exercise

• Slow component of oxygen debt with half

time about 15 min
• Matches decline of blood lactate
• With brief
b i f maximal
i l exercise
i lactate
l t t is
i
produced without PCr depletion (2b fibres)
• Moderate exercise after maximal exercise
speeds lactate metabolism by up to 40%

59 60

10
 Oxygen deficit - lactate
Exercise to exhaustion
lactate and potassium
two exhausting bouts of exercise
Lactate
second exhaustion
venous
arterial
Lactate is a poor predictor of fatigue:
in the second exercise bout it starts
higher and ends higher
Lactate threshold
Why is the threshold so sudden? This matters
as it reflects maximal steady-state exercise.
• muscle hypoxia (or if flow is restricted)
cardiac output and oxygen extraction limited
• lactate release greater than lactate
metabolism
• rate of glycolysis greater than mitochondial
Oxygen deficit, litres
rate
• recruitment of fast-twitch glycolytic fibres
McArdle Fig. 7.4
61 62
Lactate Threshold
incremental exercise test pH changes
• Lactic acid production leads to increased
log scale
acidity
• Shift from pH 7 to pH 6.2 gives little
change of force in isolated muscle at 30o
C
• When exercising to exhaustion, prior
linear scale intense activity leading to higher lactate
Exercise Physiology, Robergs & Roberts
levels does not substantially enhance
fatigue
63 64
Exhaustive Recovery
Potassium • Oxygen consumption shows a long (hours)
but small tail of recovery
venous first and second
• Some of this is attributed to glycogen
resynthesis (up to 24 hr for full recovery)
arterial
• Also believed to be related to NA, stress
hormones and lipid metabolism
Bansbo 1996, J Physiol 495 587
- argues that intersitial potassium
induces fatigue 65 66
11