Document 0718
 DOCN  M9480718
 TI    Effect of L-carnitine on the zidovudine-induced destruction of human
       myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro.
 DT    9410
 AU    Semino-Mora MC; Leon-Monzon ME; Dalakas MC; Neuromuscular Diseases
       Section, National Institutes of; Neurological Diseases and Stroke,
       National Institutes of Health,; Bethesda, Maryland.
 SO    Lab Invest. 1994 Jul;71(1):102-12. Unique Identifier : AIDSLINE
       MED/94315860
 AB    BACKGROUND: Zidovudine (AZT) as used in the treatment of AIDS, causes a
       mitochondrial myopathy characterized by depletion of mitochondrial DNA,
       enzymatic defects in the respiratory chain system, and accumulation of
       lipid droplets. Most of these changes are also seen in normal human
       myotubes treated with AZT. Because L-carnitine plays a major role in the
       transport of long chain fatty acids across the inner mitochondrial
       membrane and facilitates the beta-oxidation of fatty acids, we examined
       the effect of L-carnitine in preventing the destructive effect of AZT on
       the mitochondria and the myotubes of human muscle in tissue culture.
       EXPERIMENTAL DESIGN: Myotubes, prepared from human muscle biopsies, were
       exposed to various concentrations of AZT for up to 3 weeks. One-third of
       the flasks were treated with AZT alone, another third with AZT plus
       L-carnitine and another third were untreated. The cultures were
       evaluated with: (a) immunocytochemistry counting the number of myotubes
       stained with antibodies to Leu-19; (b) enzyme histochemistry for NADH
       reaction and oil-red-O stain to assess mitochondrial enzymatic activity
       and lipid droplet accumulation; and (c) electron microscopy counting all
       the organelles within representative sections of the myotubes, at
       x24,000, and calculating the volumetric density of each organelle/unit
       volume of tissue. RESULTS: AZT, at concentrations 250 microM and above,
       caused depopulation of the Leu-19-positive myotubes, destructive changes
       in the mitochondria consisting of swelling, lamellar inclusions and
       multiple concentric cristae, accumulation of lipid droplets, and
       increase lysosomes. L-Carnitine increased the number of Leu-19-positive
       myotubes from 3.4 +/- 0.6 to 9.4 +/- 1.2, preserved the morphology of
       the mitochondria, increased their volumetric density from 2.5 +/- 0.4 to
       6.0 +/- 0.7, and reduced the volumetric density of the lipid droplets
       from 12.2 +/- 4.9 to 1.4 +/- 0.7 and of the lysosomes from 15.6 +/- 3.6
       to 3.9 +/- 1.4 (p < 0.001). CONCLUSIONS: L-Carnitine, used concurrently
       with AZT, prevents the human myotubes from the AZT-associated
       destruction, preserves the structure and volume of mitochondria and
       prevents the accumulation of lipids. The findings may have potential
       clinical implications in preventing the myotoxicity of AZT in patients
       with AIDS.
 DE    Carnitine/*PHARMACOLOGY  Dose-Response Relationship, Drug
       Histocytochemistry  Human  Immunohistochemistry  Mitochondria,
       Muscle/*DRUG EFFECTS/ULTRASTRUCTURE  Mitochondrial Myopathies/CHEMICALLY
       INDUCED  Muscles/*DRUG EFFECTS/ULTRASTRUCTURE  Reproducibility of
       Results  Stains and Staining  Tissue Culture  Zidovudine/*ADVERSE
       EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).