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Regulation of Mitochondrial Oxygen Consumption at Exercise Onset: O 2 delivery or O 2 utilization?

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.

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Regulation of Mitochondrial Oxygen Consumption at Exercise Onset: O 2 delivery or O 2 utilization?

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  1. Regulation of Mitochondrial Oxygen Consumption at Exercise Onset:O2 delivery or O2 utilization? F.W. Kolkhorst Kasch Exercise Physiology Lab San Diego State University, San Diego, CA

  2. Why study VO2 kinetics? Grassi et al., JAP, 1996

  3. VO2 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 PmitO2 is not saturating in all active muscle fibers at all time points

  5. 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)

  6. VO2 response to electrical stimulation in isolated canine muscleThere 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)

  7. O2 deficit during electrical stimulation in isolated canine muscleBlood 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).

  8. 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)

  9. Effect of Cr supplementation on VO2 kinetics during heavy exercise Shedden et al., unpublished observations

  10. Effect of Cr supplementation on repeated bouts of supramaximal cycling O2D in the later bouts was 15% greater after Cr supplementation (P = 0.040) * Kolkhorst et al., unpublished observations

  11. 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

  12. 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

  13. 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

  14. Bout 2 Bout 1 Top: VO2 responses to repeated bouts of supra-LT exercise. Bottom: VO2 responses to repeated bouts of sub-LT exercise. Gerbino et al., JAP, 1996

  15. 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

  16. Hypotheses Bicarbonate ingestion would: slow rapid component decrease magnitude of slow component Purpose To investigate effects of bicarbonate ingestion on VO2 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 VT • 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] • VO2 measured breath-by-breath • used 5-s averages in analysis

  18. Three-component model of VO2 kinetics Phase I Phase II Phase III 3 A'3 2 VO2 A'2 1 A'1 VO2base TD2 TD3 Time Initiation of exercise VO2(t) = VO2base + A1 • (1-e-(t-TD1)/1) + A2• (1-e-(t-TD2/2) + A3• (1-e-(t-TD3)/3)

  19. Pre-exercise blood measurements (mean  SE) * P < 0.001

  20. VO2 kinetics from heavy exercise (mean  SE) * P < 0.05

  21. VO2 response to heavy exercise in a representative subject Kolkhorst et al., MSSE, 2004

  22. 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

  23. 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

  24. 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)

  25. 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

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

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