TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model

Inflammatory responses in the heart that are driven by sustained increases in cytokines have been associated with several pathological processes, including cardiac hypertrophy and heart failure. Emerging data suggest a link between cardiomyopathy and myocardial metabolism dysregulation. To further elucidate the relationship between a pro-inflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumour necrosis factor-α (TNF-α). Exposure of AC16 cells to TNF-α inhibited the expression of peroxisome proliferator-activated receptor coactivator 1α (PGC-1α), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-α, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1α expression in the heart compared with that of control mice. The mechanism by which TNF-α reduced PGC-1α expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-κB pathways. PGC-1α downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 expression and depended on the DNA-binding activity of both peroxisome proliferator-activated receptor β/δ and estrogen-related receptor α transcription factors. These results point to PGC-1α downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.