Regulation of the activity of the
pyruvate dehydrogenase complex in skeletal muscle plays an important role in fuel selection and
glucose homeostasis. Activation of the complex promotes disposal of
glucose, whereas inactivation conserves substrates for hepatic
glucose production.
Starvation and diabetes induce a stable increase in
pyruvate dehydrogenase kinase activity in skeletal muscle mitochondria that promotes phosphorylation and inactivation of the complex. The present study shows that these metabolic conditions induce a large increase in the expression of PDK4, one of four
pyruvate dehydrogenase kinase isoenzymes expressed in mammalian tissues, in the mitochondria of gastrocnemius muscle. Refeeding starved rats and
insulin treatment of diabetic rats decreased
pyruvate dehydrogenase kinase activity and also reversed the increase in PDK4
protein in gastrocnemius muscle mitochondria.
Starvation and diabetes also increased the abundance of PDK4
mRNA in gastrocnemius muscle, and refeeding and
insulin treatment again reversed the effects of
starvation and diabetes. These findings suggest that an increase in amount of this
enzyme contributes to hyperphosphorylation and inactivation of the
pyruvate dehydrogenase complex in these metabolic conditions. It was further found that feeding rats
WY-14,643, a selective agonist for the
peroxisome proliferator-activated receptor-alpha (
PPAR-alpha), also induced large increases in
pyruvate dehydrogenase kinase activity, PDK4
protein, and PDK4
mRNA in gastrocnemius muscle. Since long-chain
fatty acids activate
PPAR-alpha endogenously, increased levels of these compounds in
starvation and diabetes may signal increased expression of PDK4 in skeletal muscle.