Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia

Jeffrey S. Wilson, Greg Rushing, Brad L. Johnson, Jeffrey Kline, Martin R. Back, Dennis F. Bandyk

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The purpose of this study was to evaluate the effects of dichloroacetate sodium (DCA), a drug that inactivates pyruvate dehydrogenase kinase (PDH-K), on pyruvate dehydrogenase (PDH) activity, lactate level, and function of skeletal muscle in an experimental model of acute limb ischemia. Thirty-two male Sprague-Dawley rats underwent right iliac artery ligation to produce hindlimb ischemia. After 2 hours of ischemia, 16 animals received intravenous DCA (15 mg/100 g body weight) and 16 control animals received an equivalent volume of normal saline. After an additional 1 hour of ischemia (total 3 hours) tibialis anterior muscle from the ischemic limb and contralateral nonischemic limb was excised, rapidly freeze-clamped with Wallenberg tongs cooled in liquid nitrogen, and stored at -70°C. Muscles specimens were subsequently assayed for PDH activity and lactate level by use of spectrophotometric techniques. An additional 16 animals (DCA-treated, n = 8; control, n = 8) underwent ex-vivo gastrocnemius muscle fatigue testing with a 10 g tension preload after 3 hours of limb ischemia. In ischemic hind limbs, DCA treatment significantly (p = 0.025) increased PDH activity (19.6 ± 1.6 μmol/min/g dry weight) compared to controls (13.1 ± 1.3 μmol/min/g dry weight). DCA treatment did not increase (p = 0. 13) skeletal muscle PDH activity in the nonischemic limbs (9.6 ± 1.1 μmol/min/g dry weight, controls; 13.2 ± 1.3 μmol/min/g dry weight, DCA group). In DCA-treated animals, hind limb ischemia resulted in no significant increase in muscle lactate levels compared to the nonischemic limb, while control animals demonstrated a significant (p = 0.005) elevation in lactate level in ischemic limbs compared to contralateral nonischemic limb. Ischemia induced a significant decrease in time to muscle fatigue in both DCA-treated and control animals (p = 0.002 and 0.001, respectively). Time to muscle fatigue in DCA-treated animals was increased compared to controls (2.6 ± 0.3 versus 2 ± 0.6 minutes; p <0.05) in ischemic limbs but was not significantly different in nonischemic limbs (DCA = 3.3 ± 0.5 minutes; control = 3.1 ± 0.6 minutes). Treatment with DCA during acute limb ischemia reduced the depression of PDH activity and lactate level of skeletal muscle. Ischemic muscle function was also improved by DCA treatment. Further investigation of the potential beneficial effects of DCA treatment on muscle injury during ischemia and reperfusion is warranted.

Original languageEnglish (US)
Pages (from-to)191-195
Number of pages5
JournalVascular and Endovascular Surgery
Volume37
Issue number3
StatePublished - May 2003
Externally publishedYes

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Dichloroacetic Acid
Pyruvic Acid
Oxidoreductases
Skeletal Muscle
Ischemia
Extremities
Muscle Fatigue
Muscles
L-Lactate Dehydrogenase
Weights and Measures
Lactic Acid
Iliac Artery
Hindlimb

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Wilson, J. S., Rushing, G., Johnson, B. L., Kline, J., Back, M. R., & Bandyk, D. F. (2003). Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia. Vascular and Endovascular Surgery, 37(3), 191-195.

Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia. / Wilson, Jeffrey S.; Rushing, Greg; Johnson, Brad L.; Kline, Jeffrey; Back, Martin R.; Bandyk, Dennis F.

In: Vascular and Endovascular Surgery, Vol. 37, No. 3, 05.2003, p. 191-195.

Research output: Contribution to journalArticle

Wilson, JS, Rushing, G, Johnson, BL, Kline, J, Back, MR & Bandyk, DF 2003, 'Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia', Vascular and Endovascular Surgery, vol. 37, no. 3, pp. 191-195.
Wilson, Jeffrey S. ; Rushing, Greg ; Johnson, Brad L. ; Kline, Jeffrey ; Back, Martin R. ; Bandyk, Dennis F. / Dichloroacetate increases skeletal muscle pyruvate dehydrogenase activity during acute limb ischemia. In: Vascular and Endovascular Surgery. 2003 ; Vol. 37, No. 3. pp. 191-195.
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abstract = "The purpose of this study was to evaluate the effects of dichloroacetate sodium (DCA), a drug that inactivates pyruvate dehydrogenase kinase (PDH-K), on pyruvate dehydrogenase (PDH) activity, lactate level, and function of skeletal muscle in an experimental model of acute limb ischemia. Thirty-two male Sprague-Dawley rats underwent right iliac artery ligation to produce hindlimb ischemia. After 2 hours of ischemia, 16 animals received intravenous DCA (15 mg/100 g body weight) and 16 control animals received an equivalent volume of normal saline. After an additional 1 hour of ischemia (total 3 hours) tibialis anterior muscle from the ischemic limb and contralateral nonischemic limb was excised, rapidly freeze-clamped with Wallenberg tongs cooled in liquid nitrogen, and stored at -70°C. Muscles specimens were subsequently assayed for PDH activity and lactate level by use of spectrophotometric techniques. An additional 16 animals (DCA-treated, n = 8; control, n = 8) underwent ex-vivo gastrocnemius muscle fatigue testing with a 10 g tension preload after 3 hours of limb ischemia. In ischemic hind limbs, DCA treatment significantly (p = 0.025) increased PDH activity (19.6 ± 1.6 μmol/min/g dry weight) compared to controls (13.1 ± 1.3 μmol/min/g dry weight). DCA treatment did not increase (p = 0. 13) skeletal muscle PDH activity in the nonischemic limbs (9.6 ± 1.1 μmol/min/g dry weight, controls; 13.2 ± 1.3 μmol/min/g dry weight, DCA group). In DCA-treated animals, hind limb ischemia resulted in no significant increase in muscle lactate levels compared to the nonischemic limb, while control animals demonstrated a significant (p = 0.005) elevation in lactate level in ischemic limbs compared to contralateral nonischemic limb. Ischemia induced a significant decrease in time to muscle fatigue in both DCA-treated and control animals (p = 0.002 and 0.001, respectively). Time to muscle fatigue in DCA-treated animals was increased compared to controls (2.6 ± 0.3 versus 2 ± 0.6 minutes; p <0.05) in ischemic limbs but was not significantly different in nonischemic limbs (DCA = 3.3 ± 0.5 minutes; control = 3.1 ± 0.6 minutes). Treatment with DCA during acute limb ischemia reduced the depression of PDH activity and lactate level of skeletal muscle. Ischemic muscle function was also improved by DCA treatment. Further investigation of the potential beneficial effects of DCA treatment on muscle injury during ischemia and reperfusion is warranted.",
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