Regulation of Mitochondrial Oxygen Consumption at Exercise Onset: O 2 delivery or O 2 utilization? F.W. Kolkhorst Kasch Exercise Physiology Lab San Diego.

Regulation of Mitochondrial Oxygen Consumption at Exercise Onset:

O2 delivery or O2 utilization?

F.W. KolkhorstKasch Exercise Physiology Lab

San Diego State University, San Diego, CA

Why study VO2 kinetics?

Grassi et al., JAP, 1996

VO2 response to heavy exercise in a representative subject

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Time (s)

VO2 (

L·m

in-1

)

Residuals

Kolkhorst et al., MSSE, 2004

What is primary regulator of mitochondrial respiration at exercise onset?

• Oxygen utilization? (Grassi et al.)

– infers metabolic inertia• Oxygen delivery? (Hughson & Morrisey, JAP, 1982)

– infers that PmitO2 is not saturating in all active muscle fibers at all time points

Regulation of mitochondrial respiration:O2 utilization (metabolic inertia)?

Peripheral O2 diffusion (capillary-to-mitochondria) as a limiting factor?

• hyperoxic air had no effect on VO2 kinetics (MacDonald et al., JAP 1997)

PO2 in isolated canine muscle had no effect on VO2 kinetics (Grassi et al., JAP 1998)

VO2 response to electrical stimulation in isolated canine muscle

There were no differences in the time constant between the three conditions. (RSR13 is a drug that shifts O2-Hb dissociation curve to the right) (Grassi et al., JAP 1998)

O2 deficit during electrical stimulation in isolated canine muscle

Blood flow enhanced with administration of adenosine was compared to control. O2D was ~25% less during enhanced blood flow at high-intensity stimulation (Grassi et al., 1998, 2000).

Effect of Cr supplementation on VO2 kinetics

• no effect on VO2 response after supplementation (Balsom et al., 1993; Stroud et al.

1994) rapid component amplitude during

exercise >VT after supplementation (Jones et al., 2002)

• faster kinetics after supplementation (Rico-Sands & Mendez-Marco, 2000)

Placebo Creatine

Pre-treatment

Post-treatment

Pre-treatment

Post-treatment

2 (s) 21.9 8.3 19.2 8.3 28.4 7.9 24.5 7.3

A'2 (Lmin-1) 1.86 0.44 1.89 0.39 1.92 0.48 1.89 0.49

VO2diff6-3 (Lmin-1 ) 2.00 1.52 1.94 1.04 2.28 1.26 2.30 1.24

MRT (s) 65.1 13.2  63.3 12.1

59.8 15.9 62.5 14.0

Shedden et al., unpublished observations

Effect of Cr supplementation on VO2 kinetics during heavy exercise

O2D in the later bouts was 15% greater after Cr supplementation (P = 0.040)

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Bout

O2 D

efic

it (L

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Creatine-preCreatine-post

*

Kolkhorst et al., unpublished observations

Effect of Cr supplementation on repeated bouts of supramaximal cycling

Regulation of mitochondrial respiration:O2 utilization (metabolic inertia)?

Potential mechanisms• Pyruvate dehydrogenase complex (PDH)

– pharmacological intervention spared PCr during exercise transition (Timmons et al., AJP, 1998)

• PCr/Cr– Cr will and PCr will mitochondrial respiration in

vitro (Walsh et al., 2002)• when PCr:Cr was decreased from 2.0 (resting) to 0.5

(low-intensity), small in respiration• when PCr:Cr was further decreased to 0.1 (high-

intensity), large in respiration

Regulation of mitochondrial respiration:O2 delivery?

Can O2 supply during entire adaptation phase precisely anticipate/exceed O2 demand? (Hughson et al., ESSR, 2001)

– feed forward control from motor cortex/skeletal muscle and CV control center

– matching steady-state O2 delivery requires feedback control mechanisms

Effects of prior exercise on VO2 kinetics

Light warmup exercise – no affect on VO2 kinetics of subsequent bout

Heavy warmup exercise (Bohnert et al., Exp Physiol, 1998; Gerbino et al., JAP, 1996)

– speeded VO2 kinetics

– metabolic acidosis thought to enhance O2 delivery

Top: VO2 responses to repeated bouts of supra-LT exercise.

Bottom: VO2 responses to repeated bouts of sub-LT exercise.

Bout 2Bout 1

Gerbino et al., JAP, 1996

Effects of prior exercise on VO2 kinetics

• later studies suggested that warmup bouts affected only slow component amplitude, not the kinetics (Burnley et al., 2000, 2001)

– used more sophisticated analyses of VO2 kinetics– no effect on rapid component time constant

• breathing hypoxic air slows VO2 kinetics• breathing hyperoxic air speeds VO2 kinetics

at exercise >VT (MacDonald et al., 1997)

– faster MRT, O2D, Phase III amplitude

HypothesesBicarbonate ingestion would:1. slow rapid component2. decrease magnitude of slow component

PurposeTo investigate effects of bicarbonate ingestion on VO2 kinetics

Methods

• 10 active subjects (28 9 yr; 82.4 11.2 kg) • On separate days, performed two 6-min bouts

at 25 W greater than VT

– ingested 0.3 gkg-1 body weight of sodium bicarbonate with 1 L of water or water only

• Measured pre-exercise blood pH and [bicarbonate]

• VO2 measured breath-by-breath– used 5-s averages in analysis

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Time (s)

VO2 (

L/m

in)

Raw data

5-s averages

Three-component model of VO2 kinetics

2

3

1

TD2

A'3

A'2

A'1VO2base

Phase I Phase II

Time

VO2

Initiation of exercise

TD3

Phase III

VO2(t) = VO2base + A1 • (1-e-(t-TD1)/1)+ A2 • (1-e-(t-TD2/2)+ A3 • (1-e-(t-TD3)/3)

Pre-exercise blood measurements (mean SE)

* P < 0.001

Control trial Bicarbonate trialpH 7.43 0.01 7.51 0.01*

HCO3- (mmol·L-1) 26 1 33 1*

Base excess (mmol·L-1)

2 1 11 1*

VO2 kinetics from heavy exercise (mean SE)

Control BicarbonateA'2 (mLmin-1) 1444 177 1597 198

TD2 (s) 27.3 3.5 27.2 3.7

2 (s) 20.8 2.4 27.9 3.5*

A'3 (mLmin-1) 649 53 463 43*

TD3 (s) 98.9 11.9 127.5 14.1

3 (s) 244.8 50.5 132.1 21.5

ΔVO2(6-3) (mLmin-1) 302 36 253 40* P < 0.05

VO2 response to heavy exercise in a representative subject

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0 60 120 180 240 300 360

Time (s)

VO2 (

L·m

in-1

)

Residuals

Kolkhorst et al., MSSE, 2004

Discussion

• Bicarbonate altered manner in which VO2 increased– slower rapid component– smaller slow component

• Why did bicarbonate affect slow component?– bicarbonate attenuates decreases in muscle pH (Nielsen

et al., 2002; Stephens et al., 2002)– Does pH cause fatigue?

• Westerblad et al. (2002) suggested Pi accumulation primary cause

• bicarbonate ingestion performance

Why did bicarbonate affect rapid component?– alkalosis decreased vasodilation and caused leftward

shift of O2-Hb dissociation curve– effects of prior heavy exercise on rapid component are

equivocal 2 and MRT (MacDonald et al., 1997; Rossiter et al., 2001;

Tordi et al., 2003)• n/c in 2, but A'2 and A'3 (Burnley et al., 2001; Fukuba et al.,

2002)

Why did bicarbonate affect slow component?– bicarbonate attenuates decreases in muscle pH (Nielsen

et al., 2002; Stephens et al., 2002)– Does pH cause fatigue?

• Westerblad et al. (2002) suggested Pi accumulation primary cause

• bicarbonate ingestion performance

Potential effects of bicarbonate ingestion on slow component

• Slow component may reflect increased motor unit recruitment– fatigue may be due to metabolic acidosis

• Nonsignificant tendencies of smaller ΔVO2(6-3) after bicarbonate ingestion (Santalla et al., 2003; Zoladz et al., 1998)

Pulmonary VO2 kinetics are known to be:

• faster in trained than untrained• faster during exercise with predominantly ST

fibers than FT fibers• slower after deconditioning• slower in aged population• slower in patients with respiratory/CV

diseases as well as in heart and heart/lung transplant recipients

VO2 kinetics appears to be more sensitive than VO2max or LT to perturbations such as exercise training

What is primary regulator of mitochondrial respiration at exercise onset?

• Oxygen utilization?• Oxygen delivery?