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

Why study VO 2 kinetics? Grassi et al., JAP, 1996

VO 2 response to heavy exercise in a representative subject 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 P mit O 2 is not saturating in all active muscle fibers at all time points

Regulation of mitochondrial respiration: O 2 utilization (metabolic inertia)? Peripheral O 2 diffusion (capillary-to-mitochondria) as a limiting factor? hyperoxic air had no effect on VO 2 kinetics (MacDonald et al., JAP 1997)  P O 2 in isolated canine muscle had no effect on VO 2 kinetics (Grassi et al., JAP 1998)

VO 2 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 O 2 -Hb dissociation curve to the right) (Grassi et al., JAP 1998)

O 2 deficit during electrical stimulation in isolated canine muscle Blood flow enhanced with administration of adenosine was compared to control. O 2 D was ~25% less during enhanced blood flow at high- intensity stimulation (Grassi et al., 1998, 2000).

Effect of Cr supplementation on VO 2 kinetics no effect on VO 2 response after supplementation (Balsom et al., 1993; Stroud et al. 1994)  rapid component amplitude during exercise >V T after supplementation (Jones et al., 2002) faster kinetics after supplementation (Rico-Sands & Mendez-Marco, 2000)

PlaceboCreatine Pre- treatment Post- treatment Pre- treatment Post- treatment  2 (s)21.9     7.3 A' 2 (L  min -1 )1.86     0.49 VO 2diff6-3 (L  min -1 )2.00     1.24 MRT (s) 65.1     14.0 Shedden et al., unpublished observations Effect of Cr supplementation on VO 2 kinetics during heavy exercise

O 2 D in the later bouts was 15% greater after Cr supplementation (P = 0.040) * Kolkhorst et al., unpublished observations Effect of Cr supplementation on repeated bouts of supramaximal cycling

Regulation of mitochondrial respiration: O 2 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: O 2 delivery? Can O 2 supply during entire adaptation phase precisely anticipate/exceed O 2 demand? (Hughson et al., ESSR, 2001) –feed forward control from motor cortex/skeletal muscle and CV control center –matching steady-state O 2 delivery requires feedback control mechanisms

Effects of prior exercise on VO 2 kinetics Light warmup exercise –no affect on VO 2 kinetics of subsequent bout Heavy warmup exercise (Bohnert et al., Exp Physiol, 1998; Gerbino et al., JAP, 1996) –speeded VO 2 kinetics –metabolic acidosis thought to enhance O 2 delivery

Top: VO 2 responses to repeated bouts of supra-L T exercise. Bottom: VO 2 responses to repeated bouts of sub-L T exercise. Bout 2 Bout 1 Gerbino et al., JAP, 1996

Effects of prior exercise on VO 2 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 VO 2 kinetics –no effect on rapid component time constant breathing hypoxic air slows VO 2 kinetics breathing hyperoxic air speeds VO 2 kinetics at exercise >V T (MacDonald et al., 1997) –faster MRT,  O 2 D,  Phase III amplitude

Hypotheses Bicarbonate ingestion would: 1.slow rapid component 2.decrease magnitude of slow component Purpose To investigate effects of bicarbonate ingestion on VO 2 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 V T –ingested 0.3 g  kg -1 body weight of sodium bicarbonate with 1 L of water or water only Measured pre-exercise blood pH and [bicarbonate] VO 2 measured breath-by-breath –used 5-s averages in analysis

Three-component model of VO 2 kinetics 22 33 11 TD 2 A' 3 A' 2 A' 1 VO 2base Phase IPhase II Time VO 2 Initiation of exercise TD 3 Phase III VO 2(t) = VO 2base + A 1 (1-e -(t-TD1)/  1 ) + A 2 (1-e -(t-TD2/  2 ) + A 3 (1-e -(t-TD3)/  3 )

Pre-exercise blood measurements (mean  SE) * P < Control trialBicarbonate trial pH 7.43   0.01* HCO 3 - (mmol·L -1 ) 26  133  1* Base excess (mmol·L -1 ) 2  111  1*

VO 2 kinetics from heavy exercise (mean  SE) ControlBicarbonate A' 2 (mL  min -1 )1444   198 TD 2 (s) 27.3   3.7  2 (s)20.8   3.5* A' 3 (mL  min -1 )649   43* TD 3 (s) 98.9   14.1  3 (s)244.8   21.5 ΔVO 2 (6 -3) (mL  min -1 )302   40 * P < 0.05

VO 2 response to heavy exercise in a representative subject Kolkhorst et al., MSSE, 2004

Discussion Bicarbonate altered manner in which VO 2 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 O 2 -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 ΔVO 2(6-3) after bicarbonate ingestion (Santalla et al., 2003; Zoladz et al., 1998)

Pulmonary VO 2 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 VO 2 kinetics appears to be more sensitive than VO 2max or L T to perturbations such as exercise training

What is primary regulator of mitochondrial respiration at exercise onset? Oxygen utilization? Oxygen delivery?