Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays an important role in cell growth and metabolism. mTOR has been postulated as a nutrient sensor, but its role in the regulation of fatty acid and glucose metabolism is poorly understood. For the first time, we show that mTOR inhibition in skeletal muscle cells has pronounced effects on intermediary metabolism. Rapamycin, a uniquely specific mTOR inhibitor with clinical applications, increased fatty acid oxidation by 60% accompanied by increased activities of carnitine palmitoyltransferases I and II, the former believed to be the primary intracellular regulatory enzyme of the fatty acid oxidation pathway. Furthermore, glucose transport capacity, glycogen synthesis, and glycolysis were reduced by approximately 40% under the same conditions. In addition, in the presence of rapamycin, hyperinsulinemic conditions (100 nmol/L insulin, 24 hours) were unable to suppress fatty acid oxidation in L6 myotubes. Rapamycin treatment also decreased baseline phosphorylation of mTOR residues S2448 and S2481 by 30% and almost completely abolished p70 S6 kinase phosphorylation. These results show that rapamycin causes a metabolic shift from glucose utilization to fatty acid oxidation in model muscle cells in the presence of nutrient abundance and underline the importance of mTOR as a key regulator in glucose and lipid metabolism.
Sipula
Ian J
IJ
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Brown
Nicholas F
NF
Perdomo
German
G
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D005227:Fatty Acids; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus