energy supplies and control

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Energy Supplies and

Control of MuscleMetabolism

1

BL0224 Physiological Control

KCL ICHS ©2008

The Problem

• Muscle avidly consumes ATP using

actomyosin ATPase and Ca2+ pumpATPase

2

• ,

increases more than 100-fold

• If ATP were depleted muscle would go into

rigour (rigor mortis)

The Solution

• Have a range of mechanisms for supplying

ATP according to needs of speed and

endurance

3

•

cell

• Make sure that a range of fatigue

mechanisms exist!

External Supplies

GlucoseFatty

acids

muscle

4

ADP + Pi ►ATP

O2

CO2

Lactate

Internal Supplies

Glycogen

(2%)

Lipid

Droplets

(1%)

Creatine phosphate

(7% osmotic volume)

5

mitochondria

ATP

Internal Pathways

GlycogenLipid

Droplets

Creatine phosphate

6

mitochondria pyruvatelactate

Lohmann LipolysisGlycolysis

aerobic

ATP

anaerobic



Oxygen Uptake Kinetics

trained

Trained subject not only

has larger VO2 max butthe uptake occurs much

faster, 26sec time

constant c.f. 45sec inuntrained subject.

Caputo. Eur J Appl Physiol 93 87(2004)

7

Aerobic metabolismtakes up to 1 min to

fully activate – thusbrief exercise must be

supported byanaerobic metabolism

Limiting Timescales of Fuel Sources

Aerobic

Anaerobic

8

This diagram is realistic only for maximal exercise resulting in

fatigue at the time plotted. Exercise Physiology , Robergs & Roberts

Phosphocreatine

• Lohmann reaction (creatine kinase) acts

as a temporal buffer for ATP

• Acts as a pH buffer

9

• Acts as a spatial buffer to move ~P from

mitochondria to cross-bridge

• Pi release stimulates glycolysis

• Regulated [ADP] drives Krebs cycle

• High Pi induces fatigue

Nuclear magnetic resonance of P

CrP

CrPCrP

Pi

ATP

10rest

moderate

exercise

heavy

exercise

Pi

Pi

The anaerobic reactions

pH buffer (Lohmann)

11Jones & Round

Net reaction of A + B

PCr ► Cr + Pi + energyi.e. from

glycogen

Lohmann Reaction (1939)ADP + CrP + H+ ATP + Cr

creatine kinase

• k = 100 so CrP acts asa buffer for ATP

• ADP held low rising to

12

0.2 mM in fatigue

[ADP] ~ [creatine]/500

• CrP acts as pH buffer

• CrP acts as spatialbuffer to move ATPfrom mitochondria tomyosin



The Phosphocreatine Shuttle

13Maughan & Gleeson

ATP movement

Effects of Creatine Supplementation

1: Faster Aerobic

Recovery

2: Prolonged

Anaerobic

Endurance

[ATP].[creatine]

[ADP].[PCr] =K[ADP] ~ creatine/500

14J F Clark (1997) J Athl Train 32: 45–51.

Creatine and Phosphocreatine: A Review

of Their Use in Exercise and Sport

3: Decreased Deamination

2 ADP ► ATP+ AMP

(myokinase; AMP►ammonia)

Twenty grams per day of creatine can be added to the

athlete's diet for 1 to 2 weeks and reduced to 5 g/day

for the remainder of the sports season.

Phosphocreatine Resynthesis

31P NMR

in vivo human

Rarkevicius 1998

15Maughan & Gleeson

Recovery

within 2 min

Needs blood

flow to

removelactate

Glycogen

• Glycogen content is 2% - 4% of muscle

• Stores 100 - 200 mM hexose

• Exhaustion correlates well with glycogen

16

depletion (this will lead to PCr depletion)

• Slow repletion

• Both depletion and high CHO diet lead to

greater storage of glycogen

Basic Muscle Metabolism

cell

glucose

glycogen glucose-6P phosphorylase

fatty acids

insulin noradrenaline

Cr + Pi

PCr

A c t o m y o s i n

A T P a s e

PCr use leads to

glycogen breakdown

17

pyruvate

acetyl coA

KREBS

CYCLE

lactic acid

mitochondria

NAD+

NADH

mitochondria

lipid

33 ATP

3 ATP

CO2

Phosphorylase

(glycogen breakdown)

stimulated by:

• inor anic hos hate – from Lohman

18

• free calcium – from activation

• noradrenaline via cAMP – prolonged

exercise



Glycogen Contentduring high intensity cycling

F a t i g u e

19Maughan & Gleeson

s a t 7 0 mi n

Glycogen Recoveryis very slow

60

70

mM hexose

20

0

10

20

30

40

Rest 1 hr

exercise

+1 hr +2hr

Saltin 1999 JP 514 293

Glycogen Recoveryfollowing one-legged exhaustive exercise

Exercise induces

enhanced glycogen

storage

21

Bergstrom 1966

Takes about a

day to recover!

Diet, Glycogen & Endurance

High CHO

diets can

double both

glycogen

storage and

duration to

22

exhaustion

3 day normal diet

finally 3 day high CHO

then 3 day low CHO

23

Carbohydrate Loading

• 1966 Bergstrom - supercompensation

• 1967 Bergstrom – carbohydrate loading

• 1969 Marathon won by Ron Hill using

24

depletion then loading carbohydrate diet

• Current practice

Reduce training load and increase

carbohydrate for last few days – ‘pasta

parties’



Is Carbo-loading as Effective for Women as it is for Men?

Tarnopolsky et al (1995) –Men can increase muscle glycogen by 41%

(P<0.05) in a carbo-loading protocol whereas women did not increase

muscle glycogen.

Tarnopolsky et al (2001) –Compare

loading and exercise. HAB = habitual

diet.

25

Tarnopolsky J Appl Physiol

78:1360, 1995.

Tarnopolsky J Appl Physiol91:225, 2001.

Anaerobic Metabolismand Lactate

• Prolonged high force contractions use fast

glycolytic fibres (IIb) where ATP use is faster than mitochondria can supply

•

26

• Lactate transports out of cell and is used by

cardiac muscle and other muscle cells

• Provides only 3ATP per glycogen hexose and

costs 5 ATP to rebuild

Rate limiting

Needs NAD+

27

You don’t need to know

the individual steps!

Needs ADP

Glycolytic IntermediatesG6P increases

Rate-

limiting

step

28

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 andlactate, 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,

dihydroxyacetone phosphate; αGP, α-glycerophosphate; Lac, lactate. (Redrawn from the data of Edwards et al 1972.)

Glycolysis Products

• pyruvate

• ATP

• NADH

29

pyruvate + NADH ◄► lactate + NAD+

(Gibbs free energy, ΔG ~ 0)

(lactate is a response to acid)

10l a c t a t e ,mM

Lactate Removal

Rate Enhanced

50% by active

recovery at

~30% VO2max

300

5

0 15 Time, min 30

7 min

exercise

65%

0%

35%

Active recovery, %VO2max

McArdle Fig. 7.1



Lactate flux during exercise of

a glycogen-depleted leg

lactate absorbed by depleted leg

31Saltin. J Physiol (1999), 514 293-302

Lactate exported by

non-depleted leg

Slow fibres have

lots of MCT1

lactate transporter

(km = 3.5 mM) sosaturates and acts

as H+ regulator or

for lactate uptake

Lactate Transporters in Slow and Fast Fibres

32Photomicrographs of immunofluorescence labeling of MCT1 (A, B) and MCT4 (C, D) in the EDL (extensor

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.

Fast fibres have lots of

MCT4 lactate transporter

(km = 35 mM) so act to

export even high levels of

lactate from muscle

lactate

Oxidative Metabolism

• Traditional view of ‘the wall’ as glycogendepletion

• Slow build-up of fatty acid oxidation

33

(noradenaline ↑, insulin ↓ )

• Glucose entry by GLUT4 transporter whichhas high Km (5 mM) promoted by insulin andinhibited by glucose-6P

Unfit person

first burns

glycogen

Fit erson

Bicycle ergometer at 55% max.

Schrauwen-Hinderling

J Appl Physiol 95: 2328, 2003

Slow onset of

lipolysis

34

rapidly

uses

lipolysis

Maughan & Gleeson

Glycogen

Depletion

Lactatedepressed in

trained person

Plasma fatty acidsenhanced in trained

person

35

Chronic activity strongly decreases

glycolytic enzymesMitochondrial enzymes

increase

36

Phosphofructokinase is rate-

limiting for glycolysis

weeks



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

37

–

• Production of acetyl CoA from FFA oxidationinhibits pyruvate dehydrogenase (glycolysis)

• 42% energy loss in resynthesis of lipid

• Type I (slow) fibres / moderate exercise useFFAs

Plasma Noradrenaline

note slow rise acting as stimulant to metabolism, especially lipolysis

3860 min bicycle ergometer; Saltin 1999 J Physiol 514 293

exercise

Growth Hormone

GH aids switch to lipolysis as well as tissue growth stimulant


Plasma Insulin

exercise induces an increased sensitivity to insulin,

allowing long-term depression of insulin


Basic Muscle Metabolism

cell

glucose

glycogen glucose-6P phosphorylase

fatty acids

insulin noradrenaline

Cr + Pi

PCr

A c t o m y o s i n

A T P a s e

Hormonal changes in

exercise ↓ glucose use,

↑ fatty acid use

41

pyruvate

acetyl coA

KREBS

CYCLE

lactic acid

mitochondria

NAD+

NADH

mitochondria

lipid

33 ATP

3 ATP

CO2

Lipid is preferred fuel

as acetyl coA inhibits

pyruvate use

lipid is dominant fuel

at normal exercise rates

42



Training increases lipid use

43

Training decrease glycogen use

44

Muscle Energetics

45

“ muscle is a machine for converting

food into work - and it tastes good

too”

Energy Efficiency

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

• CHO ► ATP 50% (mainly mitochondrial loss)

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

46

• CHO ◄► lipid 58%

• CHO ◄► glycogen 60%

so internal storage as lipid or glycogen adds ~40% to energy cost

Energy Cost

mls oxygen per metre

(on treadmill)

47

distribution of speeds

chosen by horse

Energetics of fast and slow twitch

muscles of the mouse

Force -

velocity

diagram

Slow muscle has

more curved force-

velocity diagram

48Barclay 1993, J Physiol 472 61

fast (EDL)

slow (soleus)



shortening

Fenn Curvesenergy output (measured as heat production)

increases during shortening

i.e. increased cross-bridge turnover

49

heat production

slow muscle has low isometric metabolism

Mechanical Power Efficiency

(enthalpic efficiency)

w / (h + w)

Can fit these to cross-bridgeSlow fibres optimal

at low speed / high

force

50

model:Soleus EDL

Attachment, /s 34 175

Detachment, /s 9 44

Soleus is not only slower but its cross-

bridges detaches relatively slowly.

What is efficiency?

• work efficiencyforce x distance / metabolic cost

- mechanical power output c.f. ATP rate (~ 50%)

- ~

51

- . .

• load efficiency = ‘economy’force x time / metabolic cost

- isometric metabolic rate

What is energy?

Enthalpy (H)

• change in energy

content in a chemical

reaction

Gibbs Free Energy (G)

• energy available for

doing external work

• the non-free art is

52

• liberated as heat (h)

and/or work (w)

ΔH = h + w

locked in internal

shape changes,

entropy (S)

• ΔH = ΔG - T ΔS

Energy Cost of Metabolism

Aerobic glycolysisAerobic metabolism, following a brief anaerobic contraction, is associated with recovery heat equalin 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 33moles ATP per hexose.

Cost o f l co en s tor a e ~ 4 0%

53

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,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 anaerobicactivity 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).

Metabolic Recovery

• Oxygen deficit and debt

• Alactic and lactic recovery and pH

• Lactate metabolism

54

• Recovery from exhaustive exercise

ICHS 2008



Deficit and recovery from light exercise

oxygen deficit

55

McArdle Fig 7.9

“oxygen debt”

Oxygen Debti.e. oxygen uptake after exercise

• Recovery of oxygen stores (myoglobin) is

fast and small• During moderate exercise there is a

56

(1.5x) recovery oxygen debt

• Fast time course (30s half time) that

matches phosphocreatine resynthesis

Oxygen

Debt

(630.7 ml)

Elderly people walking at 1 mph

57

J Gerontology A58:M734-M739

Oxygen-Uptake (VO2) Kinetics and Functional

MobilityPerformance in Impaired Older Adults

Neil B. Alexander (2003)

Oxygen Deficit - CrP

58McArdle Fig. 7.4

Heavy exercise & lactate

• Slow component of oxygen debt with half

time about 15 min

• Matches decline of blood lactate

59

• With brief maximal exercise lactate is

produced without PCr depletion (2b fibres)

• Moderate exercise after maximal exercise

speeds lactate metabolism by up to 40%

Deficit and recovery from heavy exercise

60



Oxygen deficit - lactate

61

Oxygen deficit, litres

McArdle Fig. 7.4

Lactate threshold

Why is the threshold so sudden? This matters

as it reflects maximal steady-state exercise.

• muscle hypoxia (or if flow is restricted)

62

• lactate release greater than lactate

metabolism

• rate of glycolysis greater than mitochondial

rate

• recruitment of fast-twitch glycolytic fibres

Lactate Thresholdincremental exercise test

log scale

63

linear scale

Exercise Physiology , Robergs & Roberts

pH changes

• Lactic acid production leads to increased

acidity

• Shift from pH 7 to pH 6.2 gives little

64

C

• When exercising to exhaustion, prior

intense activity leading to higher lactate

levels does not substantially enhance

fatigue

Exercise to exhaustionlactate and potassium

two exhausting bouts of exerciseLactate Potassium

venous

second exhaustionvenous first and second

65

arterialarterial

Lactate is a poor predictor of fatigue:

in the second exercise bout it starts

higher and ends higher Bansbo 1996, J Physiol 495 587

- argues that intersitial potassium

induces fatigue

Exhaustive Recovery

• Oxygen consumption shows a long (hours)

but small tail of recovery

• Some of this is attributed to glycogen

66

• Also believed to be related to NA, stress

hormones and lipid metabolism

energy supplies and control

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