title: Rapid Repression of ADP Transport by Palmitoyl-CoA Is Attenuated by Exercise Training in Humans: A Potential Mechanism to Decrease Oxidative Stress and Improve Skeletal Muscle Insulin Signaling.
abstract: Mitochondrial ADP transport may represent a convergence point unifying two prominent working models for the development of insulin resistance, as reactive lipids (specifically palmitoyl-CoA [P-CoA]) can inhibit ADP transport and subsequently increase mitochondrial reactive oxygen species emissions. In the current study, we aimed to determine if exercise training in humans diminished P-CoA attenuation of mitochondrial ADP respiratory sensitivity. Six weeks of exercise training increased whole-body glucose homeostasis and skeletal muscle Akt signaling and reduced markers of oxidative stress without reducing maximal mitochondrial H2O2 emissions. To ascertain if enhanced mitochondrial ADP transport contributed to the improvement in the in vivo oxidative state, we determined mitochondrial ADP sensitivity in the presence and absence of P-CoA. In the absence of P-CoA, exercise training reduced mitochondrial ADP sensitivity. In contrast, exercise training increased mitochondrial ADP sensitivity with P-CoA present. We further show that P-CoA noncompetitively inhibits mitochondrial ADP transport and the ability of ADP to attenuate mitochondrial H2O2 emission. Altogether, the current data provide a potential mechanism for how P-CoA contributes to insulin resistance and highlight the ability of exercise training to diminish P-CoA attenuation in mitochondrial ADP transport.
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Alison
authors.initials: A
authors.lastname: Ludzki
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Eric A F
authors.initials: EA
authors.lastname: Herbst
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Allison
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: George J
authors.initials: GJ
authors.lastname: Heigenhauser
authors.affiliation: East Carolina Diabetes and Obesity Institute, Departments of Physiology and Kinesiology, East Carolina University, Greenville, NC.
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada ghollowa@uoguelph.ca.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism*; D064797:Physical Conditioning, Human / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D010171:Palmitoyl Coenzyme A; D000244:Adenosine Diphosphate; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
references.citation: Am J Physiol Endocrinol Metab. 2000 Sep;279(3):E554-60
references.pmid: 10950822
references.citation: Am J Physiol Cell Physiol. 2006 Mar;290(3):C844-51
references.pmid: 16251473
references.citation: Biochemistry. 2014 Jun 17;53(23):3817-29
references.pmid: 24884163
references.citation: Biochem J. 2012 Nov 15;448(1):13-20
references.pmid: 22928974
references.citation: Diabetologia. 2004 Jan;47(1):23-30
references.pmid: 14673522
references.citation: J Biol Chem. 2004 Oct 1;279(40):41294-301
references.pmid: 15252018
references.citation: Mol Cell Biochem. 1994 Apr-May;133-134:155-92
references.pmid: 7808453
references.citation: J Biol Chem. 2007 Oct 26;282(43):31257-66
references.pmid: 17761668
references.citation: Diabetes Metab Rev. 1989 Dec;5(8):665-89
references.pmid: 2693017
references.citation: J Physiol. 2013 Dec 1;591(23):6089-101
references.pmid: 24081154
references.citation: Prog Lipid Res. 2006 Jan;45(1):42-72
references.pmid: 16445986
references.citation: Proc Nutr Soc. 1999 Nov;58(4):1025-33
references.pmid: 10817171
references.citation: Biochem J. 2005 Dec 1;392(Pt 2):353-62
references.pmid: 16076285
references.citation: Biochem J. 2011 Jul 15;437(2):215-22
references.pmid: 21554250
references.citation: Cell Metab. 2010 Dec 1;12(6):668-74
references.pmid: 21109199
references.citation: J Physiol. 2012 Nov 1;590(21):5475-86
references.pmid: 22907058
references.citation: Aging Cell. 2010 Dec;9(6):1032-46
references.pmid: 20849523
references.citation: Am J Physiol Endocrinol Metab. 2008 May;294(5):E882-8
references.pmid: 18319352
references.citation: Cardiovasc Res. 2008 Oct 1;80(1):20-9
references.pmid: 18558627
references.citation: Am J Physiol. 1996 Feb;270(2 Pt 1):E265-72
references.pmid: 8779948
references.citation: Eur J Biochem. 1989 Jul 1;182(3):585-92
references.pmid: 2546761
references.citation: J Physiol. 2002 Aug 15;543(Pt 1):191-200
references.pmid: 12181291
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Oct;289(4):R1144-54
references.pmid: 16020522
references.citation: Diabetes. 2004 Jan;53(1):25-31
references.pmid: 14693694
references.citation: J Biol Chem. 2010 May 28;285(22):17077-88
references.pmid: 20348099
references.citation: Cell. 2008 Feb 8;132(3):375-86
references.pmid: 18267070
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12896-901
references.pmid: 9789011
references.citation: J Biol Chem. 1987 Jul 5;262(19):9109-14
references.pmid: 3597408
references.citation: Diabetes. 2012 Dec;61(12):3148-55
references.pmid: 22961081
references.citation: Am J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E798-805
references.pmid: 22829583
references.citation: Diabetes. 2002 Oct;51(10):2959-63
references.pmid: 12351433
references.citation: Cell Metab. 2007 Mar;5(3):167-79
references.pmid: 17339025
references.citation: Diabetologia. 2014 Apr;57(4):832-40
references.pmid: 24458200
references.citation: Biochim Biophys Acta. 1974 Oct 16;369(1):86-94
references.pmid: 4278702
references.citation: Diabetes. 2002 Jul;51(7):2005-11
references.pmid: 12086926
references.citation: J Biol Chem. 2002 Nov 22;277(47):44784-90
references.pmid: 12237311
references.citation: J Physiol. 2014 Mar 15;592(6):1341-52
references.pmid: 24396061
references.citation: J Clin Invest. 2009 Mar;119(3):573-81
references.pmid: 19188683
references.citation: Diabetologia. 2011 Jun;54(6):1417-26
references.pmid: 21331471
references.citation: J Cell Physiol. 2003 Feb;194(2):186-93
references.pmid: 12494457
references.citation: FEBS Lett. 1991 Dec 9;294(3):158-62
references.pmid: 1756853
references.citation: Physiol Behav. 2008 May 23;94(2):242-51
references.pmid: 18207474
references.citation: J Biol Chem. 1971 Jan 25;246(2):402-11
references.pmid: 4250745
references.citation: IUBMB Life. 2009 Jan;61(1):47-55
references.pmid: 18839419
references.citation: J Physiol. 2001 Dec 15;537(Pt 3):971-8
references.pmid: 11744769