Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells

• Published in: The FEBS journal Vol. 272; no. 12; pp. 3004 - 3014
• Main Authors: Abbot, Emily L., McCormack, James G., Reynet, Christine, Hassall, David G., Buchan, Kevin W., Yeaman, Stephen J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.06.2005; Blackwell Publishing Ltd
• Subjects: Butyrates - pharmacology; Cell culture; Cells, Cultured; Enzymes; Fatty Acids - metabolism; Fatty Acids - pharmacology; Gene expression; Gene Expression Regulation, Enzymologic; gene regulation; Glucose - metabolism; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin - pharmacology; Isoenzymes; mitochondria; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Muscular system; Myoblasts, Skeletal - drug effects; Myoblasts, Skeletal - enzymology; Oxazoles - pharmacology; peroxisome proliferator‐activated receptor; Phenylurea Compounds - pharmacology; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; PPAR delta - agonists; PPAR delta - genetics; PPAR delta - metabolism; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; Protein Kinases - drug effects; Protein Kinases - genetics; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases; pyruvate dehydrogenase kinase; RNA, Messenger - drug effects; skeletal muscle; Thiazoles - pharmacology; Tyrosine - analogs & derivatives; Tyrosine - pharmacology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2005.04713.x

The pyruvate dehydrogenase complex occupies a central and strategic position in muscle intermediary metabolism and is primarily regulated by phosphorylation/dephosphorylation. The identification of multiple isoforms of pyruvate dehydrogenase kinase (PDK1–4) and pyruvate dehydrogenase phosphatase (PDP1–2) has raised intriguing new possibilities for chronic pyruvate dehydrogenase complex control. Experiments to date suggest that PDK4 is the major isoenzyme responsible for changes in pyruvate dehydrogenase complex activity in response to various different metabolic conditions. Using a cultured human skeletal muscle cell model system, we found that expression of both PDK2 and PDK4 mRNA is upregulated in response to glucose deprivation and fatty acid supplementation, the effects of which are reversed by insulin treatment. In addition, insulin directly downregulates PDK2 and PDK4 mRNA transcript abundance via a phosphatidylinositol 3‐kinase‐dependent pathway, which may involve glycogen synthase kinase‐3 but does not utilize the mammalian target of rapamycin or mitogen‐activated protein kinase signalling pathways. In order to further elucidate the regulation of PDK, the role of the peroxisome proliferators‐activated receptors (PPAR) was investigated using highly potent subtype selective agonists. PPARα and PPARδ agonists were found to specifically upregulate PDK4 mRNA expression, whereas PPARγ activation selectively decreased PDK2 mRNA transcript abundance. PDP1 mRNA expression was unaffected by all conditions analysed. These results suggest that in human muscle, hormonal and nutritional conditions may control PDK2 and PDK4 mRNA expression via a common signalling mechanism. In addition, PPARs appear to independently regulate specific PDK isoform transcipt levels, which are likely to impart important metabolic mediation of fuel utilization by the muscle.