Controlled cortical impact injury and craniotomy result in divergent alterations of pyruvate metabolizing enzymes in rat brain

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Abstract

Dysregulated glucose metabolism and energy deficit is a characteristic of severe traumatic brain injury (TBI) but its mechanism remains to be fully elucidated. Phosphorylation of pyruvate dehydrogenase (PDH) is the rate-limiting mitochondria enzyme reaction coupling glycolysis to the tricarboxylic acid cycle. Phosphorylation of PDH E1α1 subunit catalyzed by PDH kinase (PDK) inhibits PDH activity, effectively decoupling aerobic glycolysis whereas dephosphorylation of phosphorylated PDHE1α1 by PDH phosphatase (PDP) restores PDH activity. We recently reported altered expression and phosphorylation of pyruvate dehydrogenase (PDH) following TBI. However, little is known about PDK and PDP involvement. We determined PDK (PDK1–4) and PDP isoenzyme (PDP1–2) mRNA and protein expression in rat brain using immunohistochemistry and in situ hybridization techniques. We also quantified PDK and PDP mRNA and protein levels in rat brain following TBI using quantitative real-time PCR and Western blot, respectively. Controlled cortical impact-induced TBI (CCI-TBI) and craniotomy significantly enhanced PDK1-2 isoenzyme mRNA expression level but significantly suppressed PDP1 and PDK4 mRNA expression after the injury (4 h to 7 days). CCI-TBI and craniotomy also significantly increased PDK1–4 isoenzyme protein expression but suppressed PDP1–2 protein expression in rat brain. In summary, the divergent changes between PDK and PDP expression indicate imbalance between PDK and PDP activities that would favor increased PDHE1α1 phosphorylation and enzyme inhibition contributing to impaired oxidative glucose metabolism in TBI as well as craniotomy.

Highlights

▸ Phosphorylation of PDH inhibits PDH activity that may cause energy crisis in TBI. ▸ PDH phosphorylation is catalyzed by PDK and dephosphorylation catalyzed by PDP. ▸ TBI and craniotomy enhance PDK but suppress PDP isoenzyme expression in rat brain. ▸ In situ hybridization showed distinct patterns of PDK and PDP mRNA in rat brain. ▸ PDK and PDP may regulate glucose use in TBI/craniotomy through PDH phosphorylation

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