Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease

L.D. Calvert, R. Shelley, Sally J. Singh, P.L. Greenhaff, J. Bankart, M.D. Morgan, M.C. Steiner

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    Rationale: Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production. Objectives: This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD. Methods: A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise. Measurements and Main Results: DCA infusion reduced peak blood lactate concentration by 20% (mean [SE]; difference, 0.48 [0.11] mmol/L, P <0.001) and peak blood ammonia concentration by 15% (mean [SE]; difference, 14.2 [2.9] µmol/L, P <0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P <0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control. Conclusions: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.
    Original languageEnglish
    Pages (from-to)1090-1094
    JournalAmerican Journal of Respiratory and Critical Care Medicine
    Volume177
    Issue number10
    DOIs
    Publication statusPublished - 2008

    Fingerprint

    Chronic Obstructive Pulmonary Disease
    Lactic Acid
    Exercise
    Pyruvate Dehydrogenase Complex
    Ammonia
    Skeletal Muscle
    Muscles
    Workload
    Intravenous Infusions
    Oxygen Consumption
    Cross-Over Studies
    Adenosine Triphosphate

    Bibliographical note

    The full text is available free from the link given.

    Keywords

    • exercise limitation
    • chronic obstructive pulmonary disease
    • energy metabolism
    • dichloroacetate
    • skeletal muscle dysfunction

    Cite this

    Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease. / Calvert, L.D.; Shelley, R.; Singh, Sally J.; Greenhaff, P.L.; Bankart, J.; Morgan, M.D.; Steiner, M.C.

    In: American Journal of Respiratory and Critical Care Medicine, Vol. 177, No. 10, 2008, p. 1090-1094.

    Research output: Contribution to journalArticle

    Calvert, L.D. ; Shelley, R. ; Singh, Sally J. ; Greenhaff, P.L. ; Bankart, J. ; Morgan, M.D. ; Steiner, M.C. / Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease. In: American Journal of Respiratory and Critical Care Medicine. 2008 ; Vol. 177, No. 10. pp. 1090-1094.
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    abstract = "Rationale: Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production. Objectives: This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD. Methods: A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise. Measurements and Main Results: DCA infusion reduced peak blood lactate concentration by 20{\%} (mean [SE]; difference, 0.48 [0.11] mmol/L, P <0.001) and peak blood ammonia concentration by 15{\%} (mean [SE]; difference, 14.2 [2.9] µmol/L, P <0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P <0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control. Conclusions: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.",
    keywords = "exercise limitation, chronic obstructive pulmonary disease, energy metabolism, dichloroacetate, skeletal muscle dysfunction",
    author = "L.D. Calvert and R. Shelley and Singh, {Sally J.} and P.L. Greenhaff and J. Bankart and M.D. Morgan and M.C. Steiner",
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    TY - JOUR

    T1 - Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease

    AU - Calvert, L.D.

    AU - Shelley, R.

    AU - Singh, Sally J.

    AU - Greenhaff, P.L.

    AU - Bankart, J.

    AU - Morgan, M.D.

    AU - Steiner, M.C.

    N1 - The full text is available free from the link given.

    PY - 2008

    Y1 - 2008

    N2 - Rationale: Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production. Objectives: This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD. Methods: A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise. Measurements and Main Results: DCA infusion reduced peak blood lactate concentration by 20% (mean [SE]; difference, 0.48 [0.11] mmol/L, P <0.001) and peak blood ammonia concentration by 15% (mean [SE]; difference, 14.2 [2.9] µmol/L, P <0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P <0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control. Conclusions: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.

    AB - Rationale: Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production. Objectives: This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD. Methods: A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise. Measurements and Main Results: DCA infusion reduced peak blood lactate concentration by 20% (mean [SE]; difference, 0.48 [0.11] mmol/L, P <0.001) and peak blood ammonia concentration by 15% (mean [SE]; difference, 14.2 [2.9] µmol/L, P <0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P <0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control. Conclusions: We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.

    KW - exercise limitation

    KW - chronic obstructive pulmonary disease

    KW - energy metabolism

    KW - dichloroacetate

    KW - skeletal muscle dysfunction

    U2 - 10.1164/rccm.200707-1032OC

    DO - 10.1164/rccm.200707-1032OC

    M3 - Article

    VL - 177

    SP - 1090

    EP - 1094

    JO - American Journal of Respiratory and Critical Care Medicine

    JF - American Journal of Respiratory and Critical Care Medicine

    SN - 1073-449X

    IS - 10

    ER -