title: Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2.
abstract: Coenzyme A (CoA) is a cofactor that is central to energy metabolism and CoA synthesis is controlled by the enzyme pantothenate kinase (PanK). A transgenic mouse strain expressing human PANK2 was derived to determine the physiological impact of PANK overexpression and elevated CoA levels. The Tg(PANK2) mice expressed high levels of the transgene in skeletal muscle and heart; however, CoA was substantially elevated only in skeletal muscle, possibly associated with the comparatively low endogenous levels of acetyl-CoA, a potent feedback inhibitor of PANK2. Tg(PANK2) mice were smaller, had less skeletal muscle mass and displayed significantly impaired exercise tolerance and grip strength. Skeletal myofibers were characterized by centralized nuclei and aberrant mitochondria. Both the content of fully assembled complex I of the electron transport chain and ATP levels were reduced, while markers of oxidative stress were elevated in Tg(PANK2) skeletal muscle. These abnormalities were not detected in the Tg(PANK2) heart muscle, with the exception of spotty loss of cristae organization in the mitochondria. The data demonstrate that excessively high CoA may be detrimental to skeletal muscle function.
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Corbin
authors.affiliation: Department Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.affiliation: Department of Exercise Physiology, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Shepherd
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Stoilov
authors.affiliation: Department of Biology, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Percifield
authors.affiliation: Cell and Tissue Imaging-Electron Microscopy Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Horner
authors.affiliation: Cell and Tissue Imaging-Electron Microscopy Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.affiliation: Department of Exercise Physiology, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hollander
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.affiliation: Department of Biochemistry, West Virginia University, Morgantown, WV 26506, USA. Electronic address: roleonardi@hsc.wvu.edu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
mesh_terms: D000818:Animals; D003065:Coenzyme A / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D018737:Hand Strength / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D042967:Electron Transport Complex I; D003065:Coenzyme A
keywords: Coenzyme A; Mitochondria; Muscle; Pantothenate kinase; Transgenic mice