PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice: Effect of PDH kinase 1 compensation

Emily C. Dunford, Eric A. Herbst, Nam Ho Jeoung, William Gittings, J. Greig Inglis, Rene Vandenboom, Paul J. Leblanc, Robert Harris, Sandra J. Peters

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate oxidation in skeletal muscle. PDH is deactivated by a set of PDH kinases (PDK1, PDK2, PDK3, PDK4), with PDK2 and PDK4 being the most predominant isoforms in skeletal muscle. Although PDK2 is the most abundant isoform, few studies have examined its physiological role. The role of PDK2 on PDH activation (PDHa) at rest and during muscle stimulation at 10 and 40 Hz (eliciting low- and moderate-intensity muscle contractions, respectively) in isolated extensor digitorum longus muscles was studied in PDK2 knockout (PDK2KO) and wild-type (WT) mice (n = 5 per group). PDHa activity was unexpectedly 35 and 77% lower in PDK2KO than WT muscle (P = 0.043), while total PDK activity was nearly fourfold lower in PDK2KO muscle (P = 0.006). During 40-Hz contractions, initial force was lower in PDK2KO than WT muscle (P <0.001) but fatigued similarly to ~75% of initial force by 3 min. There were no differences in initial force or rate of fatigue during 10-Hz contractions. PDK1 compensated for the lack of PDK2 and was 1.8-fold higher in PDK2KO than WT muscle (P = 0.019). This likely contributed to ensuring that resting PDHa activity was similar between the groups and accounts for the lower PDH activation during muscle contraction, as PDK1 is a very potent inhibitor of the PDH complex. Increased PDK1 expression appears to be regulated by hypoxia inducible factor-1a, which was 3.5-fold higher in PDK2KO muscle. It is clear that PDK2 activity is essential, even at rest, in regulation of carbohydrate oxidation and production of reducing equivalents for the electron transport chain. In addition, these results underscore the importance of the overall kinetics of the PDK isoform population, rather than total PDK activity, in determining transformation of the PDH complex and PDHa activity during muscle contraction.

Original languageEnglish (US)
Pages (from-to)1487-1493
Number of pages7
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number6
DOIs
StatePublished - Jun 2011

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Muscle Contraction
Pyruvic Acid
Knockout Mice
Oxidoreductases
Muscles
Pyruvate Dehydrogenase Complex
Protein Isoforms
Skeletal Muscle
Carbohydrates
Electron Transport
pyruvate dehydrogenase (acetyl-transferring) kinase
In Vitro Techniques
Fatigue
Population

Keywords

  • Carbohydrate oxidation
  • E1a
  • E2
  • Hypoxia inducible factor-1a
  • Pyruvate dehydrogenase 1
  • Pyruvate dehydrogenase 4

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice : Effect of PDH kinase 1 compensation. / Dunford, Emily C.; Herbst, Eric A.; Jeoung, Nam Ho; Gittings, William; Inglis, J. Greig; Vandenboom, Rene; Leblanc, Paul J.; Harris, Robert; Peters, Sandra J.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 300, No. 6, 06.2011, p. 1487-1493.

Research output: Contribution to journalArticle

Dunford, Emily C. ; Herbst, Eric A. ; Jeoung, Nam Ho ; Gittings, William ; Inglis, J. Greig ; Vandenboom, Rene ; Leblanc, Paul J. ; Harris, Robert ; Peters, Sandra J. / PDH activation during in vitro muscle contractions in PDH kinase 2 knockout mice : Effect of PDH kinase 1 compensation. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2011 ; Vol. 300, No. 6. pp. 1487-1493.
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AU - Gittings, William

AU - Inglis, J. Greig

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AU - Leblanc, Paul J.

AU - Harris, Robert

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N2 - Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate oxidation in skeletal muscle. PDH is deactivated by a set of PDH kinases (PDK1, PDK2, PDK3, PDK4), with PDK2 and PDK4 being the most predominant isoforms in skeletal muscle. Although PDK2 is the most abundant isoform, few studies have examined its physiological role. The role of PDK2 on PDH activation (PDHa) at rest and during muscle stimulation at 10 and 40 Hz (eliciting low- and moderate-intensity muscle contractions, respectively) in isolated extensor digitorum longus muscles was studied in PDK2 knockout (PDK2KO) and wild-type (WT) mice (n = 5 per group). PDHa activity was unexpectedly 35 and 77% lower in PDK2KO than WT muscle (P = 0.043), while total PDK activity was nearly fourfold lower in PDK2KO muscle (P = 0.006). During 40-Hz contractions, initial force was lower in PDK2KO than WT muscle (P <0.001) but fatigued similarly to ~75% of initial force by 3 min. There were no differences in initial force or rate of fatigue during 10-Hz contractions. PDK1 compensated for the lack of PDK2 and was 1.8-fold higher in PDK2KO than WT muscle (P = 0.019). This likely contributed to ensuring that resting PDHa activity was similar between the groups and accounts for the lower PDH activation during muscle contraction, as PDK1 is a very potent inhibitor of the PDH complex. Increased PDK1 expression appears to be regulated by hypoxia inducible factor-1a, which was 3.5-fold higher in PDK2KO muscle. It is clear that PDK2 activity is essential, even at rest, in regulation of carbohydrate oxidation and production of reducing equivalents for the electron transport chain. In addition, these results underscore the importance of the overall kinetics of the PDK isoform population, rather than total PDK activity, in determining transformation of the PDH complex and PDHa activity during muscle contraction.

AB - Pyruvate dehydrogenase (PDH) plays an important role in regulating carbohydrate oxidation in skeletal muscle. PDH is deactivated by a set of PDH kinases (PDK1, PDK2, PDK3, PDK4), with PDK2 and PDK4 being the most predominant isoforms in skeletal muscle. Although PDK2 is the most abundant isoform, few studies have examined its physiological role. The role of PDK2 on PDH activation (PDHa) at rest and during muscle stimulation at 10 and 40 Hz (eliciting low- and moderate-intensity muscle contractions, respectively) in isolated extensor digitorum longus muscles was studied in PDK2 knockout (PDK2KO) and wild-type (WT) mice (n = 5 per group). PDHa activity was unexpectedly 35 and 77% lower in PDK2KO than WT muscle (P = 0.043), while total PDK activity was nearly fourfold lower in PDK2KO muscle (P = 0.006). During 40-Hz contractions, initial force was lower in PDK2KO than WT muscle (P <0.001) but fatigued similarly to ~75% of initial force by 3 min. There were no differences in initial force or rate of fatigue during 10-Hz contractions. PDK1 compensated for the lack of PDK2 and was 1.8-fold higher in PDK2KO than WT muscle (P = 0.019). This likely contributed to ensuring that resting PDHa activity was similar between the groups and accounts for the lower PDH activation during muscle contraction, as PDK1 is a very potent inhibitor of the PDH complex. Increased PDK1 expression appears to be regulated by hypoxia inducible factor-1a, which was 3.5-fold higher in PDK2KO muscle. It is clear that PDK2 activity is essential, even at rest, in regulation of carbohydrate oxidation and production of reducing equivalents for the electron transport chain. In addition, these results underscore the importance of the overall kinetics of the PDK isoform population, rather than total PDK activity, in determining transformation of the PDH complex and PDHa activity during muscle contraction.

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