Regulation of Skeletal Muscle DRP-1 and FIS-1 Protein Expression by IL-6 Signaling

Abstract EN

IL-6 signals through the ubiquitously expressed glycoprotein 130 (gp130) transmembrane protein to activate intracellular signaling that includes signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2).

Dynamin-1-like protein (DRP-1) and mitochondrial fission 1 protein (FIS-1) are key proteins in the process of mitochondrial fission and have emerged as IL-6-sensitive targets.

The purpose of this study was to examine the regulation of DRP-1 and FIS-1 expression by IL-6 and gp130 signaling in myotubes and skeletal muscle.

Fully differentiated C2C12 myotubes were treated with 100 ng of IL-6 for 24 hours in the presence of gp130siRNA, C188-9 (STAT3 inhibitor), or PD98059 (ERK1/2 inhibitor).

Male C57BL/6 (B6) and muscle-specific gp130 knockout mice (KO) had IL-6 systemically overexpressed for 2 weeks by transient transfection with 50 ng of an IL-6-expressing or control plasmid in the quadriceps muscles, and the tibialis anterior muscle was analyzed to determine systemic effects of IL-6.

IL-6 induced DRP-1 and FIS-1 expression in myotubes 124% and 82% (p=.001) and in skeletal muscle 97% and 187% (p=.001).

Myotube gp130 knockdown suppressed the IL-6 induction of DRP-1 68% (p=.002) and FIS-1 65% (p=.001).

Muscle KO suppressed the IL-6 induction of DRP-1 220% (p=.001) and FIS-1 121% (p=.001).

ERK1/2 inhibition suppressed the IL-6 induction of DRP-1 59% (p=.0003) and FIS-1 102% (p=.0001) in myotubes, while there was no effect of STAT3 inhibition.

We report that chronically elevated IL-6 can directly induce DRP-1 and FIS-1 expression through gp130 signaling in cultured myotubes and skeletal muscle.

Furthermore, ERK 1/2 signaling is necessary for the IL-6 induction of DRP-1 and FIS-1 expression in myotubes.