title: Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2gamma-deficient mice.
abstract: Group VIB Ca(2+)-independent phospholipase A(2)γ (iPLA(2)γ) is a membrane-bound iPLA(2) enzyme with unique features, such as the utilization of distinct translation initiation sites and the presence of mitochondrial and peroxisomal localization signals. Here we investigated the physiological functions of iPLA(2)γ by disrupting its gene in mice. iPLA(2)γ-knockout (KO) mice were born with an expected Mendelian ratio and appeared normal and healthy at the age of one month but began to show growth retardation from the age of two months as well as kyphosis and significant muscle weakness at the age of four months. Electron microscopy revealed swelling and reduced numbers of mitochondria and atrophy of myofilaments in iPLA(2)γ-KO skeletal muscles. Increased lipid peroxidation and the induction of several oxidative stress-related genes were also found in the iPLA(2)γ-KO muscles. These results provide evidence that impairment of iPLA(2)γ causes mitochondrial dysfunction and increased oxidative stress, leading to the loss of skeletal muscle structure and function. We further found that the compositions of cardiolipin and other phospholipid subclasses were altered and that the levels of myoprotective prostanoids were reduced in iPLA(2)γ-KO skeletal muscle. Thus, in addition to maintenance of homeostasis of the mitochondrial membrane, iPLA(2)γ may contribute to modulation of lipid mediator production in vivo.
authors.affiliation: Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Yoda
authors.forename: Keiko
authors.initials: K
authors.lastname: Hachisu
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.forename: Kotomi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuwata
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kudo
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Hara
mesh_terms: D000818:Animals; D005260:Female; D054522:Group VI Phospholipases A2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress; D011453:Prostaglandins / Q000096:biosynthesis*
chemical_list: D011453:Prostaglandins; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse