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Mechanistic insights into how advanced age moves the site of V̇ o 2 kinetics limitation upstream

2009; American Physiological Society; Volume: 108; Issue: 1 Linguagem: Inglês

10.1152/japplphysiol.01237.2009

8750-7587

David C. Poole, Timothy I. Musch,

Sports Performance and Training

INVITED EDITORIALSMechanistic insights into how advanced age moves the site of V̇o2 kinetics limitation upstreamDavid C. Poole, and Timothy I. MuschDavid C. PooleDepartments of Kinesiology and of Anatomy and Physiology, Kansas State University, Manhattan, Kansas, and Timothy I. MuschDepartments of Kinesiology and of Anatomy and Physiology, Kansas State University, Manhattan, KansasPublished Online:01 Jan 2010https://doi.org/10.1152/japplphysiol.01237.2009This is the final version - click for previous versionMoreSectionsPDF (73 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat beyond maturity, exercise tolerance declines inexorably with advancing age. Central to resolving the mechanistic bases for this phenomenon is understanding the effects of aging on the O2 transport system. This contention is based on the established and systematic age-related reduction in the maximal capacity for O2 uptake (i.e., V̇o2max) and slowing of V̇o2 kinetics at the onset of exercise (e.g., 11). Whereas it may be argued that aged individuals rarely operate at V̇o2max, any physical activity invokes a V̇o2 transient that is accompanied by sluggish V̇o2 kinetics in this population (11; Fig. 1, top). Such slowed V̇o2 kinetics compromise exercise tolerance by mandating a greater O2 deficit and thus increased perturbation of the intramyocyte milieu (i.e., Δphosphocreatine, [ADP], H+, inorganic phosphate, [glycogen]; for review, see Ref. 9). In younger and/or fitter populations the compelling weight of evidence suggests that the speed of V̇o2 kinetics at the onset of, for example, conventional cycling or running is not limited by muscle (or mitochondrial) O2 delivery per se but rather by intrinsic mitochondrial dynamics (9). However, with advanced age a slowing in the dynamics of O2 delivery may shift this balance upstream to a site proximal to the mitochondria.Fig. 1.The markedly slowed oxygen uptake (V̇o2) kinetics present in older individuals [top; redrawn from Scheuermann et al. (11)] may be caused by an age-related emergence of slowed (and reduced) arteriolar vasodilation in highly oxidative locomotory muscles as suggested by the finding of Behnke and Delp (1) (middle) of an endothelium-mediated impairment of arteriolar vasodilation kinetics in response to increased luminal flow (as shown for the red gastrocnemius; redrawn from Fig. 2 of Ref. 1) and ACh application (not shown). These observations provide a key link to understanding how aging might slow pulmonary and muscle V̇o2 kinetics by shifting the control of V̇o2 kinetics upstream into the O2 transport pathway [bottom; adapted from Poole et al. (9)]. Note that, in health, young individuals have relatively fast V̇o2 kinetics (top and bottom) and occupy a position to the right of the dashed line (bottom) in the non-O2 delivery-limited region, i.e., they are O2 delivery independent under normal circumstances. In contrast, old individuals may be subject to an O2 delivery limitation such that their V̇o2 kinetics become slowed by the inability of the vascular system to increase mitochondrial O2 delivery fast enough. This slowing of V̇o2 kinetics in old individuals is believed to be responsible, in part, for the compromised exercise tolerance symptomatic of advanced age in humans and animals.Download figureDownload PowerPointSeveral observations provide clues regarding the mechanisms of this age-related emergence of O2 delivery limitation of V̇o2 kinetics. These include the following. 1) Whereas mitochondrial function may decline in older individuals (4), it is preserved in excess of the capacity for O2 delivery at least until late middle/early old age (3), during which time V̇o2 kinetics are slowing progressively. 2) The demonstration by Musch and colleagues (8) that, irrespective of bulk blood flow and O2 delivery to the exercising limbs, advanced age may incur a redistribution of O2 delivery away from more oxidative muscle fibers. 3) At the onset of contractions capillary red blood cell flux in muscles from aged individuals may not increase as observed in their younger counterparts (5) such that the dynamic balance between O2 delivery and V̇o2 is compromised and microvascular O2 pressures fall to extremely low levels (2), impairing blood-myocyte O2 flux as dictated by Fick's law.The study by Behnke and Delp (1) in this issue of the Journal of Applied Physiology builds on these observations and the demonstration that advanced age impairs the ability of arteriolar smooth muscle in skeletal muscles to relax and facilitate vasodilation (6, 12). Specifically, they tested the hypothesis that aging would blunt the speed of arteriolar vasodilation preferentially in oxidative muscles and that this would occur via impaired NO-mediated endothelial processes. This endeavor necessitated a unique combination of high temporal fidelity tracking of arteriolar vasodilation in isolated vessels from rat soleus and the red and white gastrocnemius muscles and state-of-the art modeling to extract the signatory kinetics parameters. Their finding that advanced age slowed both the flow and ACh-induced magnitude and rate of arteriolar vasodilation in the oxidative muscles (soleus and red gastrocnemius) to less than one-half that present in young adults (Fig. 1, middle; Ref. 1) supports a key role for endothelium-mediated impairment of arteriolar function and thus V̇o2 kinetics in aged muscle. Interestingly this age-related effect was not present when exogenous NO was applied via sodium nitroprusside, indicating that smooth muscle function remained intact. Also, the dynamics of arteriolar vasodilation to exogenous ACh, which were far slower in the low-oxidative white gastrocnemius from young animals, were not significantly impacted by the aging processes. This observation may help explain why in old vs. young animals the low-oxidative muscles receive proportionally more, and the highly oxidative muscles less, of the available blood flow and O2 delivery than their highly oxidative counterparts (8).These results as summarized above help to close the loop in our understanding of the mechanistic bases for slowed V̇o2 kinetics in aged individuals and explain how the site of limitation to V̇o2 kinetics might shift upstream from the mitochondria (O2 utilization) to O2 transport and delivery (Fig. 1, bottom). Another important contribution of the Behnke and Delp (1) investigation is that it frames clear hypotheses to be addressed in the many disease conditions, including congestive heart failure, Type II diabetes, and chronic obstructive pulmonary disease (for review, see Ref. 10), where the speed of V̇o2 kinetics is markedly impaired and this impairment may play a deterministic role in the exercise intolerance pathognomonic to these diseases. It is also pertinent that V̇o2 kinetics in aged individuals can be markedly speeded by interventions such as a single bout of prior exercise (i.e., priming) and also as a result of exercise training (11; for review see Ref. 7). Whether these interventions speed V̇o2 kinetics and improve muscle function, and thus exercise tolerance, by upregulating the dynamics of arteriolar dilation is an important question with far-reaching therapeutic possibilities that deserves to be addressed.REFERENCES1. Behnke BJ , Delp MD. Aging blunts the dynamics of vasodilation in isolated skeletal muscle resistance vessels. J Appl Physiol (October 1, 2009). doi: 10.1152/japplphysiol.00970.2009.ISI | Google Scholar2. Behnke BJ , Delp MD , Dougherty PJ , Musch TI , Poole DC. Effects of aging on microvascular oxygen pressures in rat skeletal muscle. Respir Physiol Neurobiol 146: 259–68, 2005.Crossref | PubMed | ISI | Google Scholar3. Betik AC , Hepple RT. Determinants of V̇o2max decline with aging: an integrated perspective. Appl Physiol Nutr Metab 33: 130–140, 2008.Crossref | PubMed | ISI | Google Scholar4. Conley KE , Amara CE , Jubrias SA , Marcinek DJ. Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Exp Physiol 92: 333–339, 2007.Crossref | PubMed | ISI | Google Scholar5. Copp SW , Ferreira LF , Herspring KF , Musch TI , Poole DC. The effects of aging on capillary hemodynamics in contracting rat spinotrapezius muscle. Microvasc Res 77: 113–119, 2008.Crossref | ISI | Google Scholar6. Delp MD , Behnke BJ , Spier SA , Wu G , Muller-Delp JM. Ageing diminishes endothelium-dependent vasodilatation and tetrahydrobiopterin content in rat skeletal muscle arterioles. J Physiol 586: 1161–1168, 2008. Crossref | PubMed | ISI | Google Scholar7. Jones AM , Koppo K. edited by , Jones AM , Poole DC Effects of training on V̇o2 kinetics and performance. In: Oxygen Uptake Kinetics in Sport, Exercise and Medicine, London: Routledge, 2005, p. 373–397.Google Scholar8. Musch TI , Eklund KE , Hageman KS , Poole DC. Altered regional blood flow responses to submaximal exercise in older rats. J Appl Physiol 96: 81–88, 2004.Link | ISI | Google Scholar9. Poole DC , Barstow TJ , McDonough P , Jones AM. Control of oxygen uptake during exercise. Med Sci Sports Exerc 40: 462–474, 2008.Crossref | PubMed | ISI | Google Scholar10. Poole DC , Kindig CA , Behnke BJ. V̇o2 kinetics in different disease states. In: Oxygen Uptake Kinetics in Sport, Exercise and Medicine, edited by , Jones AM , Poole DC, London: Routledge, 2005, p. 353–372.Google Scholar11. Scheuermann BW , Bell C , Paterson DH , Barstow TJ , Kowalchuk JM. Oxygen uptake kinetics for moderate exercise are speeded in older humans by prior heavy exercise. J Appl Physiol 92: 609–616, 2002.Link | ISI | Google Scholar12. Sindler AL , Delp MD , Reyes R , Wu G , Muller-Delp JM. Effects of ageing and exercise training on eNOS uncoupling in skeletal muscle resistance arterioles. J Physiol 587: 3885–3897, 2009.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. C. Poole, Dept. of Anatomy and Physiology, College of Veterinary Medicine, Kansas State Univ., Manhattan, KS 66506-5802 (e-mail: poole@vet.ksu.edu). 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