title: Age-related impairments in skeletal muscle PDH phosphorylation and plasma lactate are indicative of metabolic inflexibility and the effects of exercise training.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, Ohio University, Athens, Ohio; Ohio Musculoskeletal and Neurological Institute, Ohio University, Athens, Ohio; Diabetes Institute, Ohio University, Athens, Ohio; consitt@ohio.edu.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Consitt
authors.affiliation: Department of Biomedical Sciences, Ohio University, Athens, Ohio;
authors.forename: Gunjan
authors.initials: G
authors.lastname: Saxena
authors.affiliation: Department of Biological Sciences, Ohio University, Athens, Ohio;
authors.forename: Alicson
authors.initials: A
authors.lastname: Saneda
authors.affiliation: Department of Kinesiology, Human Performance Laboratory, East Carolina University, Greenville, North Carolina; and East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism*; D015444:Exercise; D005260:Female; D015309:Glucose Clamp Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D010807:Physical Endurance; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D055070:Resistance Training; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: age; pyruvate dehydrogenase