title: Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice.
abstract: In extrahepatic tissues lipoprotein lipase (LPL) hydrolyzes triglycerides thereby generating FFA for tissue uptake and metabolism. To study the effects of increased FFA uptake in muscle tissue, transgenic mouse lines were generated with a human LPL minigene driven by the promoter of the muscle creatine kinase gene. In these mice human LPL was expressed in skeletal muscle and cardiac muscle, but not in other tissues. In proportion to the level of LPL overexpression, decreased plasma triglyceride levels, elevated FFA uptake by muscle tissue, weight loss, and premature death were observed in three independent transgenic mouse lines. The animals developed a severe myopathy characterized by muscle fiber degeneration, fiber atrophy, glycogen storage, and extensive proliferation of mitochondria and peroxisomes. This degree of proliferation suggests that FFA play an important role in the biogenesis of these organelles. Our experiments indicate that LPL is rate limiting for the supply of muscle tissue with triglyceride-derived FFA. Improper regulation of muscle LPL can lead to major pathological changes and may be important in the pathogenesis of some human myopathies. Muscle-specific LPL transgenic mouse lines will serve as a useful animal model for the investigation of myopathies and the biogenesis of mitochondria and peroxisomes.
authors.affiliation: Institute of Medical Biochemistry, Karl-Franzens University, Graz, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: H
authors.initials: H
authors.lastname: Radner
authors.forename: A
authors.initials: A
authors.lastname: Walsh
authors.forename: R
authors.initials: R
authors.lastname: Stollberger
authors.forename: G
authors.initials: G
authors.lastname: Knipping
authors.forename: G
authors.initials: G
authors.lastname: Hoefler
authors.forename: W
authors.initials: W
authors.lastname: Sattler
authors.forename: P H
authors.initials: PH
authors.lastname: Weinstock
authors.forename: J L
authors.initials: JL
authors.lastname: Breslow
authors.forename: R
authors.initials: R
authors.lastname: Zechner
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000235:genetics; D004790:Enzyme Induction; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005813:Genes, Synthetic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics*; D008136:Longevity; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008830:Microbodies / Q000473:pathology*; D008931:Mitochondria, Muscle / Q000473:pathology*; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D014280:Triglycerides / Q000097:blood; D015431:Weight Loss
chemical_list: D005230:Fatty Acids, Nonesterified; D009124:Muscle Proteins; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D003402:Creatine Kinase; D008071:Lipoprotein Lipase; D005947:Glucose