Using immunoblot analysis with antibodies raised against recombinant pyruvate dehydrogenase kinase (PDK) isoenzymes PDK2 and PDK4, we demonstrate selective changes in PDK isoenzyme expression in slow-twitch versus fast-twitch skeletal muscle types in response to prolonged (48 h) starvation and refeeding after starvation. Starvation increased PDK activity in both slow-twitch (soleus) and fast-twitch (anterior tibialis) skeletal muscle and was associated with loss of sensitivity of PDK to inhibition by pyruvate, with a greater effect in anterior tibialis. Starvation significantly increased PDK4 protein expression in both soleus and anterior tibialis, with a greater response in anterior tibialis. Starvation did not effect PDK2 protein expression in soleus, but modestly increased PDK2 expression in anterior tibialis. Refeeding for 4 h partially reversed the effect of 48-h starvation on PDK activity and PDK4 expression in both soleus and anterior tibialis, but the response was more marked in soleus than in anterior tibialis. Pyruvate sensitivity of PDK activity was also partially restored by refeeding, again with the greater response in soleus. It is concluded that targeted regulation of PDK4 isoenzyme expression in skeletal muscle in response to starvation and refeeding underlies the modulation of the regulatory characteristics of PDK in vivo. We propose that switching from a pyruvate-sensitive to a pyruvate-insensitive PDK isoenzyme in starvation (a) maintains a sufficiently high pyruvate concentration to ensure that the glucose → alanine → glucose cycle is not impaired, and (b) may ‘spare’ pyruvate for anaplerotic entry into the tricarboxylic acid cycle to support the entry of acetyl-CoA derived from fatty acid (FA) oxidation into the tricarboxylic acid cycle. We further speculate that FA oxidation by skeletal muscle is both forced and facilitated by upregulation of PDK4, which is perceived as an essential component of the operation of the glucose-FA cycle in starvation.
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Research Article|
March 07 2000
Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression
Mary C. SUGDEN;
Mary C. SUGDEN
1
*Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London E1 4NS, U.K.
1To whom correspondence should be addressed, at Department of Diabetes and Metabolic Medicine, Medical Sciences Building, Queen Mary and Westfield College, Mile End Road, London E1 4NS, U.K. (e-mail m.c.sugden@;qmw.ac.uk).
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Alexandra KRAUS;
Alexandra KRAUS
*Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London E1 4NS, U.K.
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Robert A. HARRIS;
Robert A. HARRIS
†Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5122, U.S.A.
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Mark J. HOLNESS
Mark J. HOLNESS
*Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London E1 4NS, U.K.
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Publisher: Portland Press Ltd
Received:
October 22 1999
Revision Received:
December 07 1999
Accepted:
January 06 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 346 (3): 651–657.
Article history
Received:
October 22 1999
Revision Received:
December 07 1999
Accepted:
January 06 2000
Citation
Mary C. SUGDEN, Alexandra KRAUS, Robert A. HARRIS, Mark J. HOLNESS; Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of PDK isoenzyme 4 expression. Biochem J 15 March 2000; 346 (3): 651–657. doi: https://doi.org/10.1042/bj3460651
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