1. 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

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

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

4. 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

5. 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)

6. 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)

7. 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).

8. 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)

9. PlaceboCreatine Pre- treatment Post- treatment Pre- treatment Post- treatment  2 (s)21.9  8.319.2  8.328.4  7.924.5  7.3 A' 2 (L  min -1 )1.86  0.441.89  0.391.92  0.481.89  0.49 VO 2diff6-3 (L  min -1 )2.00  1.521.94  1.042.28  1.262.30  1.24 MRT (s) 65.1  13.2 63.3  12.159.8  15.962.5  14.0 Shedden et al., unpublished observations Effect of Cr supplementation on VO 2 kinetics during heavy exercise

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 O 2 D in the later bouts was 15% greater after Cr supplementation (P = 0.040) * Kolkhorst et al., unpublished observations Effect of Cr supplementation on repeated bouts of supramaximal cycling

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

19. 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 )

20. Pre-exercise blood measurements (mean  SE) * P < 0.001 Control trialBicarbonate trial pH 7.43  0.017.51  0.01* HCO 3 - (mmol·L -1 ) 26  133  1* Base excess (mmol·L -1 ) 2  111  1*

21. VO 2 kinetics from heavy exercise (mean  SE) ControlBicarbonate A' 2 (mL  min -1 )1444  1771597  198 TD 2 (s) 27.3  3.527.2  3.7  2 (s)20.8  2.427.9  3.5* A' 3 (mL  min -1 )649  53463  43* TD 3 (s) 98.9  11.9127.5  14.1  3 (s)244.8  50.5132.1  21.5 ΔVO 2 (6 -3) (mL  min -1 )302  36253  40 * P < 0.05

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

23. 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

24. 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

25. 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)

26. 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

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