title: Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle.
abstract: Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Taddeo
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Laker
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Breen
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Y N
authors.initials: YN
authors.lastname: Akhtar
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Kenwood
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Liao
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Fazakerley
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Tomsig
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Harris
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Keller
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Chow
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Lynch
authors.affiliation: Teijin Pharma Limited, 4-3-2, Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Chokki
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, OH, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Department of Pharmacology, University of New South Wales, Sydney, NSW, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Turner
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia ; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: D E
authors.initials: DE
authors.lastname: James
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA ; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Hoehn
keywords: ANT, adenine nucleotide translocator; BKA, bongkrekic acid; CSA, cyclosporin A; CYPD, cyclophilin D; Cyclophilin D; DAG, diacylglycerol; ETC, electron transport chain; FFA, free fatty acid; Glucose; HFD, high fat diet; HK2, hexokinase 2; Insulin resistance; KO, knockout; LFD, low fat diet; MCAD, medium chain acyl-CoA dehydrogenase; MHC, myosin heavy chain; MIRKO, muscle insulin receptor knockout; MPTP, mitochondrial permeability transition pore; Mitochondrial dysfunction; Mitochondrial permeability transition pore; MnSOD, mitochondrial manganese superoxide dismutase; O2•, superoxide; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PDHa, active PDH; PDHt, total PDH; PM, plasma membrane; Rg′, rate of glucose transport; Skeletal muscle; TBARS, thiobarbituric acid reactive substances; TEM, transmission electron microscopy; VDAC, voltage-dependent anion channel; WT, wild type; [3H]-2-DOG, [3H]-2-deoxyglucose; β-HAD, β-hydroxyacyl-CoA dehydrogenase