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J Physiol (2003), 548.2, p. 334
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.035774
Email: gibalam{at}mcmaster.ca
The term 'anaplerosis' was originally coined to describe metabolic pathways which replenish a metabolic cycle (Kornberg, 1966). With respect to the tricarboxylic acid (TCA) cycle, the phenomenon refers to reactions other than citrate synthase that enrich the pool of TCA cycle intermediates (TCAI). Anaplerosis serves to counteract the loss of TCAI, i.e. removal of TCA cycle carbon as metabolites other than carbon dioxide, and these opposing processes are known to be a normal part of cellular metabolism in muscle. Our current understanding is based largely on studies conducted in the heart, where a variety of techniques including the use of isolated perfused organs, isotopic analysis of TCAI, and tracer kinetic modelling have been employed to establish that anaplerosis plays an important role in cardiac function by serving to maintain steady-state concentrations of TCAI (for references, see Gibala et al. 2000). For example, hearts perfused with ketone bodies as the sole substrate experienced a rapid and severe decline in contractile function; however, this decline was prevented by the addition of an anaplerotic substrate such as pyruvate (Russel & Taegtmeyer, 1991). These observations implied there was an 'optimal' concentration of TCAI which was required for normal contractile function, and supported the notion that the size of the TCAI pool played a regulatory role in aerobic energy metabolism.
A paper published in this issue of The Journal of Physiology by Walton and colleagues (Walton et al. 2003) provides important new insights regarding the phenomenon of anaplerosis in skeletal muscle. These authors employed 13C NMR spectroscopy to determine flux through anaplerotic pathways relative to TCA cycle flux, during both rest and electrically evoked contractions in different fibre populations of the rat hindlimb. They observed a marked and sustained increase in anaplerotic flux during contraction, which was proportional to the increased rate of fuel oxidation. In addition, the measured fibre type-specific rates of relative anaplerotic flux correlated with the oxidative capacity of the muscles (i.e. higher values in soleus and red gastrocnemius compared to white gastrocnemius). Previously, muscle TCAI concentrations had been shown to increase severalfold at the start of exercise; however, no studies had quantified the changes in anaplerotic flux that produced these effects. It was also generally accepted that the initial increase in TCAI concentration was a function of excess pyruvate availability (Wagenmakers, 1999; Gibala et al. 2000), mediated by a transient mismatch between glycolytic flux and mitochondrial pyruvate oxidation. However, if pyruvate availability was the prevailing determinant of flux through anaplerotic pathways, it would be expected that once a new metabolic steady state was reached, flux through anaplerotic pathways would revert to basal (i.e. resting) levels. The technique employed by Walton et al. (2003) - which requires that the tissue being measured is in metabolic and isotopic steady state, such that the quantities of 13C entering and exiting the TCA cycle are equal - indicates there was a sustained increase in anaplerotic flux during contraction which persisted for at least 90 min.
Unfortunately, Walton et al. (2003) did not measure muscle TCAI concentration and thus the significance of the contraction-induced increase in anaplerotic flux cannot be evaluated with respect to potential changes in the TCAI pool. As previously mentioned, the sum concentration of TCAI has been shown to increase at the start of exercise, and investigators have theorized that this increase is necessary in order to attain high rates of aerobic energy provision (for review, see Wagenmakers, 1999). The observation that TCA cycle expansion is impaired in patients with muscle phosphorylase deficiency and the fact that muscle TCAI concentrations decline with prolonged, fatiguing exercise have also been interpreted to support such a relationship. However, several recent studies have challenged the notion that alterations in the TCAI pool during muscle contraction play a regulatory role in oxidative energy delivery. For example, Bruce et al. (2001) showed that augmenting the rate of TCAI expansion during the rest-work transition did not alter muscle phosphocreatine (PCr) degradation or lactate accumulation, as might be expected if the increase in TCAI was linked to aerobic energy provision. With respect to prolonged moderate exercise, work by the present author and Danish colleagues (Gibala et al. 2002) showed that following an initial 3-fold expansion, there was a marked decrease in the muscle TCAI pool which plateaued after 60 and 90 min to a value not different from the resting concentration. Despite the decrease in TCAI concentration, mitochondrial respiration was not compromised, as evidenced by stable thigh oxygen uptake throughout the entire period of exercise and little change in muscle PCr after 10 min. Finally, a recent study (K. D. Dawson, D. J. Baker, M. J. Gibala & P. L. Greenhaff, unpublished findings) showed that acute pharmacological inhibition of TCAI expansion (using cycloserine, an inhibitor of alanine aminotransferase) did not adversely affect muscle function or metabolism during electrically evoked contractions in the rat hindlimb. These collective observations give credence to the assertion by Walton et al. (2003) that: 'it may be that the ability to sustain flux through anaplerotic pathways is more important for normal oxidative metabolism in muscle than expansion of the TCAI pool per se'.
The present work by Walton and colleagues is exciting; however, their findings also highlight several important areas which await further investigation. These include quantitative assessment of absolute changes in skeletal muscle anaplerotic flux during both rest and contraction, the significance of the apparent fibre type-specific rates of anaplerotic flux, the factors which regulate various anaplerotic pathways in muscle, and elucidation of the subcellular distribution of TCAI (i.e. mitochondrial vs. cytoplasmic compartments). Nonetheless, it would appear that with respect to the anaplerotic-induced swelling of the muscle TCAI pool during contraction, this may be one phenomenon where size does not matter.
| Bruce M, Constantin-Teodosiu D, Greenhaff PL, Boobis LH, Williams C & Bowtell JL (2001). Am J Physiol Endocrinol Metab 280, E669-675. | [Abstract/Full Text] |
| Gibala MJ, Gonzalez-Alonso J & Saltin B (2002). J Physiol 545, 705-713. | [Abstract/Full Text] |
| Gibala MJ, Young ME & Taegtmeyer H (2000). Acta Physiol Scand 168, 657-665. | [Medline] |
| Kornberg HL (1966). In Essays in Biochemistry, ed. Campbell PN & Marshall RD, pp.1-31. Academic Press, London, UK. | |
| Russel RR & Taegtmeyer H (1991). Am J Physiol 261, H1756-1762. | |
| Wagenmakers AJM (1999). In Biochemistry of Exercise X, ed. Hargreaves M & Thompson M, pp. 217-232. Human Kinetics, Champaign, IL, USA. | |
| Walton ME, Ebert D & Haller RG (2003). J Physiol 548, 541-548. | [Abstract/Full Text] |
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