Carnitine transport into muscular cells. inhibition of transport and cell growth by mildronate

• Published in: Biochemical pharmacology Vol. 59; no. 11; pp. 1357 - 1363
• Main Authors: Georges, Béatrice, Le Borgne, Françoise, Galland, Stéphane, Isoir, Muriel, Ecosse, David, Grand-Jean, Florence, Demarquoy, Jean
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2000; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Biological Transport - drug effects; carnitine; Carnitine - metabolism; Cell Division - drug effects; Cell Membrane - metabolism; Cell physiology; Cells, Cultured; Fundamental and applied biological sciences. Psychology; In Vitro Techniques; Male; Membrane and intracellular transports; Methylhydrazines - pharmacology; Mice; mildronate; Molecular and cellular biology; muscle cell; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Rats; Rats, Wistar; transport; carnitine; mildronate; transport; muscle cell; Cell proliferation; Rat; Biological transport; Rodentia; Molecular interaction; Muscular fiber; Cell differentiation; In vitro; Carnitine; Vertebrata; Mammalia; Mouse; Membrane transport; Established cell line; Myoblast
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(00)00265-3

Carnitine is involved in the transfer of fatty acids across mitochondrial membranes. Carnitine is found in dairy and meat products, but is also biosynthesized from lysine and methionine via a process that, in rat, takes place essentially in the liver. After intestinal absorption or hepatic biosynthesis, carnitine is transferred to organs whose metabolism is dependent on fatty acid oxidation, such as heart and skeletal muscle. In skeletal muscle, carnitine concentration was found to be 50 times higher than in the plasma, implicating an active transport system for carnitine. In this study, we characterized this transport in isolated rat myotubes, established mouse C2C12 myoblastic cells, and rat myotube plasma membranes and found that it was Na +-dependent and partly inhibited by a Na +/K + ATPase inhibitor. l-carnitine analogues such as d-carnitine and γ-butyrobetaine interfere with this system as does acyl carnitine. Among these inhibitors, the most potent was mildronate (3-(2,2,2-trimethylhydrazinium)propionate), known as a γ-butyrobetaine hydroxylase inhibitor. It also induced a marked decrease in carnitine transport into muscle cells. Removal of carnitine or treatment with mildronate induced growth inhibition of cultured C2C12 myoblastic cells. These data suggest that myoblast growth and/or differentiation is dependent upon the presence of carnitine.