Acetyl group availability influences phosphocreatine degradation even during intense muscle contraction

Abstract

We previously established that activation of the pyruvate dehydrogenase complex (PDC) using dichloroacetate (DCA) reduced the reliance on substrate-level phosphorylation (SLP) at the onset of exercise, with normal and reduced blood flow. PDC activation also reduced fatigue development during contraction with reduced blood flow. Since these observations, several studies have re-evaluated our observations. One study demonstrated a performance benefit without a reduction in SLP, raising a question mark over PDC's role in the regulation of ATP regeneration and our interpretation of fatigue mechanisms. Using a model of muscle contraction similar to the conflicting study (i.e. tetanic rather than twitch stimulation), we re-examined this question. Using canine skeletal muscle, one group was infused with saline while the other was pretreated with 300 mg (kg body mass) −1 DCA. Muscle biopsies were taken at rest, peak tension (1 min) and after 6 min of tetanic electrical stimulation (75 ms on−925 ms off per second) and blood flow was limited to 25% of normal values observed during contraction. DCA reduced phosphocreatine (PCr) degradation by 40% during the first minute of contraction, but did not prevent the almost complete depletion of PCr stores at 6 min, while muscle fatigue did not differ between the two groups. During intermittent tetanic stimulation PCr degradation was 75% greater than with our previous 3 Hz twitch contraction protocol, despite a similar rate of oxygen consumption at 6 min. Thus, in the present study enhanced acetyl group availability altered the time course of PCr utilization but did not prevent the decline towards depletion. Consistent with our earlier conclusions, DCA pretreatment reduces muscle fatigue only when SLP is attenuated. The present study and our met-analysis indicates that enhanced acetyl group availability results in a readily measurable reduction in SLP when the initial rate of PCr utilization is ∼1 mmol (kg dry mass) −1 s −1 or less (depending on intrinsic mitochondrial capacity). When measured early during an uninterrupted period of muscle contraction, acetyl group availability is likely to influence SLP under any condition where mitochondria are responsible for a significant proportion of ATP regeneration.

No effect of glutamine supplementation and hyperoxia on oxidative metabolism and performance during high-intensity exercise

“…In accordance with previous studies demonstrating no effect of the TCA intermediate pool size on oxidative metabolism during submaximal exercise (Bruce et al 2001;Gibala et al 2002a,b;Dawson et al 2003;Howarth et al 2004;Timmons et al 2004;Dawson et al 2005) and intense (Bangsbo et al 2006) exercise, the present results show no effect of glutamine ingestion, and thus no limiting effect of the TCA intermediate pool size, on oxidative metabolism and performance during maximal aerobic exercise. …”

“…Conversely dissociation between the TCA intermediate pool size and oxidative energy provision during exercise has been consistently demonstrated during sub-maximal exercise (Bruce et al, 2001;Gibala, Gonzalez-Alonso & Saltin, 2002a;Gibala, Peirce, Constantin-Teodosiu & Greenhaff, 2002b;Dawson, Howarth, Tarnopolsky, Wong & Gibala, 2003;Howarth, LeBlanc, Heigenhauser & Gibala, 2004;Timmons, Constantin-Teodosiu, Poucher & Greenhaff, 2004;Dawson, Baker, Greenhaff & Gibala, 2005;Bangsbo, Gibala, Howart & Krustrup, 2006). However, Gibala, MacLean, Graham & Saltin, (1998) Dichloroacetate infusion results in near-maximal activation of the pyruvate dehydrogenase complex and stockpiling of acetyl-units.…”

“…Furthermore, whilst dichloroacetate infusion reduced TCA intermediate content at rest (ConstantinTeodosiu et al, 1999) the majority of studies show no effect of prior dichloroacetate infusion on the TCA intermediate pool during exercise (Gibala et al 2002b;Timmons et al 2004). The study by Bansgbo et al (2006) Bangsbo et al (2006), the rate of oxidative ATP production and power output were enhanced during severe intensity finger flexion exercise when 6 g.day -1 of a mixture containing 55g.l -1 of malate (the TCA intermediate making the largest contribution to the increase in TCA intermediate during exercise (Gibala, Tarnopolsky, & Graham, 1997) was consumed for 15 days (Bendahan et al 2002).…”

No acetyl group deficit is evident at the onset of exercise at 90% of maximal oxygen uptake in humans

“…However, Roberts et al (Roberts et al 2002) (Timmons, Constantin-Teodosiu, Poucher, & Greenhaff, 2004) showed that phosphocreatine degradation was reduced during the first minute of intense tetanic contraction in canine skeletal muscle following dichloroacetate infusion. In contrast, other studies (Bangsbo, Gibala, Krustrup, Gonzalez-Alonso, & Saltin, 2002;Savasi, Evans, Heigenhauser, & Spriet, 2002) found no effect of prior dichloroacetate infusion on non-oxidative adenosine triphosphate provision at the onset of cycle exercise at 90%…”

“…Furthermore, it is not clear how well the data from different species, e.g. canine muscle, (Timmons et al 2004), and small muscle mass exercise (Bangsbo et al 2002;Rossiter et al 2003) compare to upright large muscle mass exercise in humans. Indeed determination of pulmonary In an attempt to resolve some of the present conflict, the purpose of the present study was therefore to determine whether the acetyl group deficit was evident at the start of exercise at 90% 2 o V  max.…”