Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in Type 2 diabetes

The delicate homeostatic balance between glucose and fatty acid metabolism in relation to whole-body energy regulation is influenced by mitochondrial function. We determined expression and regulation of mitochondrial enzymes including pyruvate dehydrogenase kinase (PDK) 4, PDK2, carnitine palmitoyltransferase 1b, and malonyl–coenzyme A decarboxylase in skeletal muscle from people with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). Vastus lateralis biopsies were obtained from NGT (n = 79) or T2DM (n = 33) men and women matched for age and body mass index. A subset of participants participated in a 4-month lifestyle intervention program consisting of an unsupervised walking exercise. Muscle biopsies were analyzed for expression and DNA methylation status. Primary myotubes were derived from biopsies obtained from NGT individuals for metabolic studies. Cultured skeletal muscle was exposed to agents mimicking exercise activation for messenger RNA (mRNA) expression analysis. The mRNA expression of PDK4, PDK2, and malonyl–coenzyme A decarboxylase was increased in skeletal muscle from T2DM patients. Methylation of the PDK4 promoter was reduced in T2DM and inversely correlated with PDK4 expression. Moreover, PDK4 expression was positively correlated with body mass index, blood glucose, insulin, C peptide, and hemoglobin A1c. A lifestyle intervention program resulted in increased PDK4 mRNA expression in NGT individuals, but not in those with T2DM. Exposure to caffeine or palmitate increased PDK4 mRNA in a cultured skeletal muscle system. Our findings reveal that skeletal muscle expression of PDK4 and related genes regulating mitochondrial function reflects alterations in substrate utilization and clinical features associated with T2DM. Furthermore, hypomethylation of the PDK4 promoter in T2DM coincided with an impaired response of PDK4 mRNA after exercise.