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1 The Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, Nottinghamshire, United Kingdom
2 Cardiovascular and Gastrointestinal Global Discovery Research Department, AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, United Kingdom
* To whom correspondence should be addressed. E-mail: Paul.Roberts{at}Unibas.ch.
We examined the effect of increasing acetylcarnitine and acetyl-CoA availability at rest, independent of pyruvate dehydrogenase complex (PDC) activation, upon routes of energy production and tension development during the rest-to-work transition in canine skeletal muscle. Our aim was to elucidate whether the lag in PDC derived acetyl-CoA delivery towards the tricarboxylic acid (TCA) cycle at the immediate onset of exercise can be overcome by increasing acetyl-group availability per se (independent of PDC activation) or is intimately dependent upon PDC derived acetyl-CoA flux. Gracilis muscle was pre-treated with saline (CON; n=6) or sodium acetate (Acetate; 360 mg kg-1 body mass, n=6) and was sampled repeatedly during 5 min of subsequent ischemic contraction. Acetate increased the availability of acetylcarnitine (P<0.01) and acetyl-CoA (P<0.01) above CON at rest and throughout contraction (P<0.05), independent of any difference in PDC activation between treatment groups at rest. Acetate reduced oxygen-independent ATP re-synthesis by ~40% (P<0.05) during the first minute of contraction. No difference in oxygen-independent ATP re-synthesis existed between treatments from 1-3 min of contraction, however, energy production via this route increased by ~25% (P<0.05) above CON in the Acetate treated group during the final 2 min of contraction. Tension development was ~20% greater after 5 min of contraction following Acetate treatment from CON (P<0.05). In conclusion, at the immediate onset of contraction, when the PDC is largely inactive, increasing cellular acetyl-group availability can overcome inertia in mitochondrial-ATP regeneration. However, following the first minute, when the PDC was near-maximally activated in both groups, it appears that PDC derived acetyl-CoA, rather than increased cellular acetyl-group availability per se, dictated mitochondrial-ATP re-synthesis.
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