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Submitted on December 5, 2005
Accepted on August 21, 2006
Department of Molecular Medicine and Surgery, and Department of Physiology and Pharmacology, Karolinska Institutet S-171 77 Stockholm, Department of Biology, Biovitrum AB, Stockholm, Sweden, Department of Medicine, Division of Cardiology, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland
* To whom correspondence should be addressed. E-mail: Anna.Krook{at}ki.se.
We identified signaling pathways by which interleukin 6 (IL6) regulates skeletal muscle differentiation and metabolism. Primary human skeletal muscle cells were exposed to IL6 (25 ng/ml either acutely or for several days) and siRNA gene-silencing was applied to measure glucose and fat metabolism. Chronic IL6 exposure increased myotube fusion and formation and the mRNA expression of GLUT4, peroxisome proliferator activated receptor (PPAR)
, PPAR
, PPAR
, PPAR coactivator 1, glycogen synthase, myocyte enhancer factor 2D, uncoupling protein 2, fatty acid transporter 4 and IL6 (P < 0.05), whereas GLUT1, CEBP and UCP3 were decreased. IL6 increased glucose incorporation into glycogen, glucose uptake, lactate production, and fatty acid uptake and oxidation, concomitant with increased phosphorylation of AMP-activated protein kinase (AMPK), STAT3 and ERK1/2. IL6 also increased PI3 kinase activity (450%; P < 0.05) which was blunted by subsequent insulin-stimulation (P < 0.05). IL6-mediated glucose metabolism was suppressed, but lipid metabolism was unaltered, by inhibition of PI3 kinase with LY294002. The siRNA-directed depletion of AMPK reduced IL6-mediated fatty acid oxidation and palmitate uptake, but not glycogen synthesis. In summary, IL6 increases glycogen synthesis via a PI3-kinase dependent mechanism and enhances lipid oxidation via an AMPK-dependent mechanism in skeletal muscle. Thus, IL6 directly promotes skeletal muscle differentiation and regulates muscle substrate utilization, promoting glycogen storage and lipid oxidation.
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