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PERSPECTIVES |
Imperial College London, Division of Biomedical Sciences, Biological Structure and Function Section, SAF-Building, London SW7 2AZ, UK
Email: t.west{at}imperial.ac.uk
It is well known that free fatty acids (FA) and carbohydrate (CHO) support muscle energy provision in mammals and that exercise intensity and endurance adaptation are key determinants of FA and CHO oxidation. Fat oxidation is highest during moderate contractions, whereas CHO oxidation is increasingly dominant at higher work rates. The pattern is similar in endurance-adapted muscle, although FA dependence increases overall because of higher muscle mitochondrial and lipid contents, and because of increased capacity to perform (e.g. sustain high running speed) at low relative exercise intensity (Brooks, 1998; Hoppeler & Flück, 2002). Mechanisms that regulate muscle FA and CHO oxidation are beginning to emerge. However, the growing array of acute (contraction-induced) and chronic (training-induced) responses to exercise attests to the extreme plasticity of skeletal muscle (Hoppeler & Flück, 2002), and suggests that the mechanisms that orchestrate fuel processing are complex. Aerobic training protocols are powerful approaches for unravelling these mechanisms because adjustments in specific pathways, signals and genes can be examined in connection with general endurance-related shifts in fuel preference.
In the current issue of The Journal of Physiology, LeBlanc et al. (2004) examined the regulation of pyruvate (i.e. CHO) oxidation after aerobic cycle-ergometer training in humans. They assayed muscle oxidative capacity, pryuvate dehydrogenase (PDH) activity, and pyruvate dehydrogenase kinase (PDK) activity in male subjects before training, and after 1 and 8 weeks post-training. Time courses for changes in total PDH and total PDK and for expression of the four isoforms of PDK are not known for one system. However, work on different species suggested to them that PDH and PDK adjustments would appear after prolonged, but not short-term, aerobic training. Key clues were that long-term training (i) increased total PDH in mice (Houle-Leroy et al. 2000), (ii) attenuated post-training PDH activity during submaximal exercise in humans (LeBlanc et al. 2003), and (iii) increased PDK activity in rats (Nakai et al. 1999). Since PDK inhibits PDH (see Fig. 1), it seemed likely that some or all of the PDK isoforms were a source of heightened post-training regulation of PDH. LeBlanc et al. (2004) reasoned that if training-induced changes in PDK isoforms were linked to the attenuated PDH activity in humans, then there should be clear indication that total PDK activity and total PDK isoforms change contemporaneously with total PDH activity.
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One consequence should be that trained muscle becomes increasingly poised to exploit elevated muscle FA reserves for energy provision. PDK-mediated control of PDH activity is in fact likely to be of general importance for the balance of FA and CHO oxidation during exercise. However, enhancement of this mechanism in more highly aerobically adapted muscle concurs with higher mitochondrial and lipid volumes, and with the capacity for trained individuals to increase performance and dependence on FA oxidation at a given level of submaximal exertion (Brooks, 1998).
LeBlanc et al. (2004) argue thoughtfully that the reason PDK2 features so prominently in post-training PDH control hinges partly on PDK2 sensitivity to (inhibition by) muscle energy imbalance. On the one hand, inhibition of PDK2 by high [ADP] and [pyruvate] during high-intensity acute exercise is favourable because this will help relieve PDH inactivation and in turn raise rates of pyruvate oxidation (Fig. 1). On the other hand, up-regulation of specifically PDK2 in response to chronic high-intensity exercise suggests that this isoform adapts to protracted perturbations in muscle energy status in order to retain control over PDH activity at higher aerobic work rates. The training responses of PDK2 label it as the ‘energy-status-sensitive’ isoform, in keeping with previous views on its role in mammalian tissues (Bowker-Kinley et al. 1998).
Increased gauging of CHO fluxes at near-maximal aerobic work rates is possibly a second consequence of the training-induced changes in PDK and PDH. Up-regulation of total PDH is undoubtedly part of the suite of chronic adaptations that increase CHO oxidation capacity after training. Together with greater PDK control over PDH activity, this means that there is increased scope for PDH activation and possibly enhanced synchrony between rates of pyruvate production and PDH activity during transitions to maximal aerobic work rate. Post-training up-regulation of chiefly PDK2 activity suggests that acute energy-sensitive control of PDH activity (Fig. 1) is increasingly important for oxidizing CHO reserves, possibly by augmenting the match between PDH activity and glycogenolysis. Tighter engagement between these pathways might also arise via increased integration of PDK2 and PDH activities with other energy-sensitive pathways involved with funnelling CHO into glycolysis, like isoforms of AMP-activated protein kinase (AMPK).
LeBlanc et al. (2004) reveal novel aspects of PDH regulation in skeletal muscle from an elegant combination of relevant molecular techniques with established training protocols. Clearly, the pay-off from such integrative experimental designs is that specific molecular features of training-induced muscle plasticity can continue to be placed into a broad and meaningful physiological context.
References
Bowker-Kinley MM et al. (1998). Biochem J 329, 191–196.[Medline]
Brooks GA (1998). Comp Biochem Physiol B 120, 89–107.[CrossRef][Medline]
Hoppeler H & Fluck M (2002). J Exp Biol 205, 2143–2152.
Houle-Leroy P et al. (2000). J Appl Physiol 89, 1608–1616.
LeBlanc PJ et al. (2003). Med Sci Sport Exerc 35, S211.
LeBlanc PJ et al. (2004). J Physiol. 557, 549–560.
Nakai N Sato Y et al. (1999). Metabolism 48, 865–869.[CrossRef][Medline]
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