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Blackwell Science, LtdOxford, UKBCPBritish Journal of Clinical Pharmacology1365-2125Blackwell Publishing 2003573237243Review ArticlePeripheral vascular disease metabolic limitationsP. L. Greenhaff DOI:10.1111/j.1365-2125.2003.01989.x Metabolic inertia in contracting skeletal muscle: a novel approach for pharmacological intervention in peripheral vascular disease P. L. Greenhaff, S. P. Campbell-O’Sullivan, D. Constantin-Teodosiu, S. M. Poucher,1 P. A. Roberts & J. A. Timmons
School of Biomedical Sciences, Centre for Integrated Systems Biology and Medicine, University of Nottingham Medical School, Queen’s
Medical Centre, Nottingham, and
1Cardiovascular and Gastrointestinal Global Discovery Research Department, AstraZeneca
Pharmaceuticals, Alderley Park, SK10 4TG, UK

Peripheral vascular disease (PVD) is generally accepted to result in the failure of skeletal muscle blood flow to increase adequately at the onset of muscular work.
There are currently no routine pharmacological interventions towards the treatment of PVD, however, recent Phase III trials in the USA have demonstrated the clinical potential of the phosphodiesterase III inhibitor Cilostazol for pain-free and maximal walking distances in patients with intermittent claudication. PVD is characterized by a marked reliance on oxygen-independent routes of ATP regeneration (phosphocre- atine hydrolysis and glycolysis) in skeletal muscle during contraction and the rapid onset of muscular pain and fatigue. The accumulation of metabolic by-products of oxygen-independent ATP production (hydrogen and lactate ions and inorganic phos- phate) has long been associated with an inhibition in contractile function in bothhealthy volunteers and PVD patients. Therefore, any strategy that could reduce thereliance upon ATP re-synthesis from oxygen-independent routes, and increase thecontribution of oxygen-dependent (mitochondrial) ATP re-synthesis, particularly at the Keywords
onset of exercise, might be expected to improve functional capacity and be of considerable therapeutic value. Historically, the increased contribution of oxygen- independent ATP re-synthesis to total ATP generation at the onset of exercise has been attributed to a lag in muscle blood flow limiting oxygen delivery during thisperiod. However, recent evidence suggests that limited inertia is present at the levelof oxygen delivery, whilst considerable inertia exists at the level of mitochondrialenzyme activation and substrate supply. In support of this latter hypothesis, we havereported on a number of occasions that activation of the pyruvate dehydrogenase Received
complex, using pharmacological interventions, can markedly reduce the dependence on ATP re-synthesis from oxygen-independent routes at the onset of muscle contrac- Accepted
tion. This review will focus on these findings and will highlight the pyruvate dehydro- genase complex as a novel therapeutic target towards the treatment of peripheralvascular disease, or any other disease state where premature muscular fatigue isprevalent due to metabolite accumulation.
(PVD). Affecting approximately 12% of the general The increasing elderly population of the western world, population [1], with an increased frequency in the dia- coupled to the greater incidence of cigarette smoking betic subpopulation [2], PVD is characterized as a fail- and poor dietary habits, has led to an increase in the ure of skeletal muscle blood flow to increase adequately clinical manifestation of peripheral vascular disease at the onset of muscular work, such as walking [3, 4].
The absence of a ‘normal’ hyperaemic response of the induced improvements differ from the normal training- cardiovascular system to exercise is associated with like adaptations that occur in healthy skeletal muscle increased reliance upon ATP re-synthesis from oxygen- independent routes (namely ATP and phosphocreatine The heavy reliance upon oxygen-independent ATP (PCr) hydrolysis and glycolysis to lactate) to meet the production at the onset of muscular contraction is a energy demands of contraction [5, 6], and the concom- symptom not solely associated with PVD muscle, but itant development of muscular pain and fatigue. The reflects an exaggeration of what occurs in healthy, nor- disease is progressive, impinging severely on the range mally perfused skeletal muscle during the transition of mobility of the patient and can ultimately jeopardize from rest to muscular work. Indeed, at the onset of the integrity of the limb (critical leg ischaemia). Indeed, skeletal muscle contraction there is a marked increase patients at this stage of the disease have a reported in energy demand which must be matched by a rapid quality of life index similar to critical–terminal phase increase in ATP re-synthesis to enable the exercise cancer patients [7]. The socio-economic impact of PVD workload to continue for longer than a few seconds.
upon the health service is immense, estimated in 1994 The re-adjustment of oxygen-dependent (mitochon- to be approximately £215 million in the UK, with drial) ATP re-synthesis to meet this demand is not approximately 60% of these costs arising from bypass immediate and follows an approximately exponential time course (for review see [19]). During this period, Clearly, any strategy capable of improving functional the shortfall in ATP supply is met by ATP re-synthesis capacity and halting disease progression could be of from oxygen-independent routes. By way of example, considerable therapeutic and economic value. Current Bangsbo et al. [20] observed in healthy human skeletal evidence, however, does not support the hypothesis that muscle that PCr hydrolysis and glycolysis contributed an improvement in peripheral blood flow results in an approximately 80% of the total ATP generated during improvement in functional capacity [9–11], a view sup- the initial 30 s of high-intensity exercise. This value ported by the lack of correlation between lower limb declined to approximately 45% during the subsequent blood flow and walking distances in PVD patients (for 60–90 s, and to approximately 30% after 120 s of exer- review see [12]). There are currently no routine pharma- cise; this decrease appeared to be accomplished by a cological interventions towards the treatment of PVD.
parallel increase in oxygen-dependent ATP re-synthesis However, the phosphodiesterase III inhibitor Cilostazol [20]. Although ATP production from oxygen-indepen- has recently demonstrated clinical potential by increas- dent routes enables rapid rates of ATP turnover to be ing both pain-free and maximal walking distance of achieved, it has only a finite capacity and also results in sufferers in Phase III trials in the USA, although the the accumulation of metabolites that are deleterious to mechanism underpinning this functional improvement muscle function (hydrogen ions, lactate ions and inor- is yet to be determined [13]. At present, the single best ganic phosphate; [21]). Indeed, without the progressive treatment strategy for patients at all levels of disease increase in mitochondrial ATP production at the onset progression is exercise training [1, 12, 14], where of contraction, and thereby the reduction in oxygen- improvements in muscular function can occur indepen- independent energy delivery, the onset of muscular dent of any measurable increase in limb blood flow [15].
fatigue would be markedly accelerated, as typified in Although the benefits of exercise training upon walking distances in PVD sufferers are well founded [9, 16, 17], Classically, the lag in oxygen-dependent ATP re- many patients find adherence to a training regime diffi- synthesis at the onset of contraction, and the resulting cult to maintain due to exercise-induced limb pain (clau- activation of oxygen-independent ATP regeneration, dication) and other disease-related complications, i.e.
has been attributed to a finite rate of increase, or inertia, heart disease, diabetes, obesity, respiratory problems in skeletal muscle blood flow and thereby oxygen [1]. The physiological adaptations that occur in skeletal delivery to contracting muscle fibres [22–24 Richard- muscle of PVD patients as a result of an exercise reha- son et al. 1995]. Indeed, the temporal changes in mus- bilitation programme have not been fully elucidated.
cle oxygen utilization at the onset of exercise closely This is due, at least in part, to studies to date not taking follow the increase in total limb blood flow during this into account the habitual activity patterns of patients period; hence the general acceptance of the phrase prior to entry into any research study, i.e. not taking into ‘oxygen deficit’ within the literature [25, 26]. Over the account any metabolic and vascular adaptations that past decade, however, there has been a growing body of might occur as a result of habitual muscle contraction evidence indicating that neither muscle blood flow [18]. In addition, it is not known if these exercise- (bulk oxygen delivery) nor capillary diffusion limit Peripheral vascular disease metabolic limitations oxygen utilization, and thereby oxygen-dependent ATP cation of PDC, either from its inactive (phosphorylated) re-synthesis, at the onset of exercise [27–29]. For to active (dephosphorylated) state by loosely associated example, Grassi et al. [28], using a blood-perfused pyruvate dehydrogenase phosphatases, or vice versa by canine gastrocnemius muscle model, demonstrated that a number of intrinsic and tissue-specific pyruvate dehy- when the delay in blood flow (and thereby oxygen drogenase kinases (Figure 1) [30, 33]. These effectors delivery) during the rest-to-steady state exercise transi- of PDC activation are sensitive to pulsatile changes in tion was eliminated, there was no further acceleration calcium availability, cellular energetics and substrate/ in the rate of increase in muscle oxygen consumption product accumulation [31, 32]. Second, the rate of pyru- over that observed under control conditions. Using the vate oxidation by PDC is regulated by end-product inhi- same model, the authors went on to present strong evi- bition of flux through the enzyme complex by NADH dence to suggest that muscle oxygen diffusion also and acetyl-CoA (Figure 1) [33]. The acetyl groups pro- does not limit muscle oxygen consumption at the onset duced by PDC can be utilized by the TCA cycle or, of exercise [29]. They concluded that the limitations to alternatively, can be stockpiled in the form of acetylcar- the rate of increase in oxygen consumption at the onset nitine, presumably when acetyl-CoA re-synthesis of exercise are probably attributable to heterogeneous exceeds its rate of utilization by citrate synthase [34].
microvascular oxygen delivery and/or an ‘intrinsic iner- Buffering acetyl groups in this way has been proposed tia’ within mitochondrial energy production of unspec- as a mechanism for the maintenance of a viable pool of free-coenzyme A, which is essential for sustained TCAcycle flux. This highlights an important metabolic role The pyruvate dehydrogenase complex: a site of
of carnitine, in addition to its function in mitochondrial metabolic inertia?
long-chain acyl group translocation [34].
Work within our laboratory over the past decade has In 1996, we were the first to demonstrate that phar- investigated the pyruvate dehydrogenase complex as a macological activation of the PDC, using the systemic potential site of limitation to mitochondrial energy pro- PDC kinase (PDK) inhibitor dichloroacetate (Figure 1) duction at the onset of muscular contraction. The pyru- [35, 36], markedly increased acetylcarnitine availability vate dehydrogenase complex (PDC) is a multienzyme in resting skeletal muscle and appreciably reduced PCr complex, located on the mitochondrial inner membrane, hydrolysis and lactate accumulation during subsequent which regulates carbohydrate entry into the tricarboxy- intense contraction, and under conditions where muscle lic acid (TCA) cycle. The PDC catalyses the physiolog- blood flow and oxygen delivery were fixed at close to ically irreversible reaction that commits carbohydrates resting levels [37]. Subsequent to this, we demonstrated to their oxidative fate inside the mitochondria through in both canine and human skeletal muscle that the rapid the conversion of the glycolytic product pyruvate into hydrolysis of PCr and accumulation of lactate that occur mitochondrial acetyl-CoA (involving NAD+ and free- at the onset of exercise were at least partly due to an coenzyme A; Figure 1). Regulation of the rate of inherent lag in the activation of oxygen-dependent formation of acetyl-CoA by the PDC (i.e. flux through (mitochondrial) ATP regeneration [38, 39]. In particular, the enzyme complex) is achieved by two strategies. The we were able to show that activation of the PDC at rest, first of these is by altering the fraction of PDC that exists using dichloroacetate, was accompanied by an approx- in its active form. This is achieved by covalent modifi- imately 30% reduction in ATP re-synthesis from oxy- Pyruvate + NAD+ + CoASH Acetyl-CoA + NADH+ + H+ + CO2
The pyruvate dehydrogenase complex reaction and covalent regulation of activation status by the intrinsic pyruvate dehydrogenase phosphatase and kinase system. CoASH, Free-coenzyme A; Pi, inorganic Magnesium (+)
(+) Magnesium
(+) Acetyl-CoA
phosphate; (–), an inhibitor of the enzyme it is Calcium (+)
(+) NADH
beside; (+), an activator of the enzyme it is beside; P, phosphorylation of the three specific serine residues Phosphatase
upon the haloenzyme core of the pyruvate (-) CoASH
dehydrogenase complex; DCA, the systemic pyruvate (-) Pyruvate
NADH (-)
(-) ADP
(-) DCA
gen-independent routes after 1 min of contraction, even any time point during contraction prior to significant though muscle force production was identical to the PDC activation. We therefore decided to test our con- saline (control) group. Following 6 min of contraction, tention that early in the rest-to-work transition period the contribution from oxygen-independent routes to there is a lag in mitochondrial ATP re-synthesis, which ATP re-synthesis had fallen to approximately 50% of is in part due to an inadequate supply of acetyl-CoA via that observed in the control group, while tension devel- PDC [43]. Using a canine hind-limb perfusion model opment was greater [38]. It also appeared from these [41], five muscle biopsy samples were obtained from the studies that some of the acetyl groups that were stock- gracilis muscle during the first minute (rest, 10, 20, 40 piled at rest after PDC activation were utilized during and 60 s) of ischaemic muscle contraction, which we contraction, indicating that the mitochondria were able envisaged would give us sufficient resolution to eluci- to utilize more acetyl groups at the onset of exercise date the temporal relationship between PDC activation, when provision was increased by dichloroacetate acetyl group accumulation, and PCr hydrolysis and lac- administration [37, 38]. From these investigations, it tate accumulation at the onset of contraction [43]. The was concluded that the activation, and thereby flux, results demonstrated that a lag in acetyl group provision through PDC must limit acetyl-CoA availability and (in the form of acetyl-CoA and acetylcarnitine) occurred consequently mitochondrial ATP re-synthesis at the during the initial 20 s of contraction, which resulted onset of exercise. Moreover, that the activation of PDC from, and was mirrored by, a lag in PDC activation and ‘priming’ of mitochondria with acetyl groups prior (Figure 2). This unequivocally demonstrated the exist- to exercise, by administering dichloroacetate, could sig- ence of a period of metabolic inertia (the so called nificantly increase the overall contribution of oxidative ‘acetyl group deficit’) in skeletal muscle at the onset of pathways to total ATP production at the onset of exer- contraction, and was directly in line with our earlier cise. Another important finding from this series of stud- observations that the supply of acetyl groups to the TCA ies was that the decline in muscle tension development cycle was limited during the rest-to-work transition [43].
during contraction (i.e. fatigue) was substantially As dichloroacetate activates the PDC and near maxi- reduced following dichloroacetate administration, prob- mally acetylates the free-coenzyme A and carnitine ably due to PCr hydrolysis and lactate accumulation pools at rest (Figure 2), it was not possible to determine being reduced at the immediate onset of contraction [37, in any of our previous studies whether the reduction in 38]. Furthermore, this effect was sustainable throughout oxygen-independent ATP re-synthesis at the onset of contraction, at least until the exercise workload was contraction following dichloroacetate (Figure 3) was increased to a near maximal intensity [39].
attributable to acetyl-CoA delivery via the PDC beingincreased at the immediate onset of contraction and/or The ‘acetyl group deficit’
was due to the readily available pool of acetyl groups If inertia in the rate of increase in oxygen-dependent being sequestered by the TCA cycle. With this question ATP regeneration at the onset of exercise does indeed in mind, we have recently investigated whether pharma- reside at the level of PDC, which our previous work cologically increasing the availability of acetyl-CoA and certainly seems to indicate, then it stands to reason that acetylcarnitine, independent of PDC activation, could a period of time must exist at the onset of exercise when overcome the acetyl group deficit at the onset of exercise acetyl-CoA supply via PDC is insufficient to match the [44]. We were able to show that administration of demands of the TCA cycle, and the concentration of sodium acetate increased the availability of acetyl-CoA acetyl-CoA should therefore decline. However, studies and acetylcarnitine in resting skeletal muscle, but did to date have shown that acetyl groups appear to accu- not increase PDC activation. Furthermore, during the mulate throughout moderate-to-intense muscular con- first minute of ischaemic muscle contraction, when the traction [34, 40–42], with this accumulation being PDC was largely inactive, treatment with sodium acetate greater in skeletal muscle contracting under ischaemic increased the contribution of oxygen-dependent ATP conditions [41]. From these findings, it has been inferred regeneration towards the energy demands of the muscle that acetyl-CoA production is probably in excess of when compared with the saline-treated (control) group TCA cycle demands throughout contraction, which con- [44]. However, following this first minute, when near trasts with our hypothesis that metabolic inertia resides maximal activation of PDC had been achieved in both at the level of PDC. Closer scrutiny of the relevant control and acetate groups, it appeared that PDC-derived literature reveals, however, that studies to date have acetyl-CoA, rather than stockpiled acetyl groups per se, failed to investigate the metabolic events occurring was the principal route of substrate delivery to the TCA within the initial seconds of contraction, or indeed, at cycle. Collectively these investigations have established Peripheral vascular disease metabolic limitations 80 100120 140 160 180 200 220 240 260 280 300 Rates of ATP re-synthesis from phosphocreatine hydrolysis and glycolysis between rest and 1 min, 1 min and 3 min and 3 and 5 min of ischaemic contraction following pretreatment with saline (CON (ᮀ)) or sodium dichloroacetate (DCA (᭿)). Results are expressed as means ± SEM, with units of mmol of ATP equivalents min kg dry muscle. Significant differences: *P < 0.05 compared with corresponding CON value 80 100 120 140 160 180 200 220 240 260 280 300 tude of oxygen-independent ATP delivery and thereby Conclusion and future perspectives
In conclusion, in the present review we have provided convincing evidence to support the contention that PDC activation and acetyl-CoA availability limit oxygen- dependent (mitochondrial) ATP re-synthesis at the onset of skeletal muscle contraction (the so called ‘acetyl group deficit’). Increasing the provision of acetylgroups, through the pharmacological activation of the PDC, can overcome this period of metabolic inertia, 80 100 120 140 160 180 200 220 240 260 280 300 accelerate the rate of mitochondrial ATP re-synthesisand concomitantly improve the maintenance of contrac- tile function throughout the rest-to-work transition Active form of the pyruvate dehydrogenase complex (PDCa) and acetyl- under both ischaemic and non-ischaemic conditions. We CoA and acetylcarnitine concentrations at rest and during 5 min of here highlight the tissue-specific activation of the pyru- ischaemic contraction following pretreatment with saline (CON (᭺)) or vate dehydrogenase complex as a potentially new and sodium dichloroacetate (DCA (᭹)). Units are as follows: PDCa, mmol of novel therapeutic target towards the treatment of periph- acetyl-CoA min-1 kg-1 dry muscle (at 37 ∞C); acetyl-CoA, mmol kg-1 dry eral vascular disease or any other disease state where muscle; acetylcarnitine, mmol kg-1 dry muscle. Results are expressed as premature muscular fatigue is prevalent due to metabo- means ± SEM. Significant differences: *P < 0.05 compared with lite accumulation, particularly as a relatively muscle- corresponding CON value; ‡P < 0.05 compared with value at rest within specific PDK isoform is now known to exist [30].
The systemic PDK inhibitor, and thereby PDC acti- vator, dichloroacetate has been used clinically for manyyears, most notably in the treatment of congenital lactic the activation of the pyruvate dehydrogenase complex acidosis (for review see [45]). However, the chronic as a rate-limiting step in the rate of rise in oxygen- administration of dichloroacetate is not known to be dependent ATP production in skeletal muscle at the without adverse side-effects. Indeed, Cicmanec et al. onset of exercise, which in turn will dictate the magni- [46] failed to establish a ‘no-adverse-effect level’ of dichloroacetate during a 90-day toxicity study in beagle characteristics in patients with unilateral arterial disease. Clin dogs. Not surprisingly, safety concerns have curtailed the use of dichloroacetate as a therapeutic agent in clin- 6 Lundgren F, Bennegard K, Elander A, Lundholm K, Schersten T, ical settings, with dichloroacetate regarded today more Bylund-Fellenius A. Substrate exchange in human limb muscle as a probe with which to investigate intermediary metab- during exercise at reduced blood flow. Am J Physiol 1988; 255: olism. Hopefully, structurally distinct [47], less toxic and tissue-specific PDK inhibitors [30] will become 7 Albers M, Fratezi AC, Deluccia N. Assessment of quality of life of available in the near future that can subsequently be patients with severe ischemia as a result of infrainguinal arterial occlusive disease. J Vasc Surg 1992; 16: 54–9.
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