PDK4
[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 4, mitochondrial precursor (EC 2.7.11.2) (Pyruvate dehydrogenase kinase isoform 4) [PDHK4]
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If fertilization does not occur for a prolonged period [i]in vivo[/i] or [i]in vitro[/i], the postovulatory oocytes will deteriorate, which called the postovulatory aging. This process disrupts the developmental competence. In the present study, we showed that the reactive oxygen species (ROS) was accumulated in oocytes during the postovulatory aging. ROS inhibited Sirt1 expression, and then increased oxidative stress by downregulating the intracellular Sirt1-FOXO3a-SOD2 axis. Moreover, the inhibited Sirt1 expression was related to the decreased mitochondrial function and the lowered level of autophagy. The mitochondrial-related apoptosis was increased by inhibiting the AKT and ERK1/2 pathways, due to the accumulation of ROS in the postovulatory oocytes. The mitochondrial pyruvate dehydrogenase kinase-4 (PDK4) can reduce ROS by inhibiting the tricarboxylic acid (TAC) cycle. We found that PDK4 was significantly decreased in the postovulatory aging oocytes. Putrescine, one of the abundant biogenic amines, ameliorated the effects of ROS and therefore improved the quality of the postovulatory aging oocytes by increasing the expression of PDK4. When PDK4 was downregulated using siRNAs, the effects of putrescine were significantly receded. We concluded that putrescine delayed the aging process of postovulatory oocytes by upregulating PDK4 expression and improving mitochondrial activity.
MeSH Terms
- Animals
- Cells, Cultured
- Cellular Senescence
- Culture Media
- Female
- Gene Expression Regulation
- Mice
- Mitochondria
- Oocytes
- Putrescine
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Keywords
- PDK4
- mitochondria
- oocyte
- postovulatory aging
- reactive oxygen species
The purpose of this study was to determine whether plasma lactate and skeletal muscle glucose regulatory pathways, specifically PDH dephosphorylation, are impaired during hyperinsulinemic conditions in middle- to older-aged individuals and determine whether exercise training could improve key variables responsible for skeletal muscle PDH regulation. Eighteen young (19-29 yr; n = 9 males and 9 females) and 20 middle- to older-aged (57-82 yr; n = 10 males and 10 females) individuals underwent a 2-h euglycemic hyperinsulinemic clamp. Plasma samples were obtained at baseline and at 30, 50, 90, and 120 min for analysis of lactate, and skeletal muscle biopsies were performed at 60 min for analysis of protein associated with glucose metabolism. In response to insulin, plasma lactate was elevated in aged individuals when normalized to insulin action. Insulin-stimulated phosphorylation of skeletal muscle PDH on serine sites 232, 293, and 300 decreased in young individuals only. Changes in insulin-stimulated PDH phosphorylation were positively related to changes in plasma lactate. No age-related differences were observed in skeletal muscle phosphorylation of LDH, GSK-3α, or GSK-3β in response to insulin or PDP1, PDP2, PDK2, PDK4, or MPC1 total protein. Twelve weeks of endurance- or strength-oriented exercise training improved insulin-stimulated PDH dephosphorylation, which was related to a reduced lactate response. These findings suggest that impairments in insulin-induced PDH regulation in a sedentary aging population contribute to impaired glucose metabolism and that exercise training is an effective intervention for treating metabolic inflexibility.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Blood Glucose
- Exercise
- Female
- Glucose Clamp Technique
- Glycogen Synthase Kinase 3
- Glycogen Synthase Kinase 3 beta
- Humans
- Insulin
- L-Lactate Dehydrogenase
- Lactic Acid
- Male
- Middle Aged
- Muscle, Skeletal
- Phosphorylation
- Physical Endurance
- Pyruvate Dehydrogenase Complex
- Resistance Training
- Young Adult
Keywords
- age
- pyruvate dehydrogenase