Rotenone inhibits primary murine myotube formation via Raf-1 and ROCK2

Sander Grefte, J.A. Wagenaars, R. Jansen, P.H. Willems, W.J.H. Koopman

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Rotenone (ROT) is a widely used inhibitor of complex I (CI), the first complex of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, particularly at high concentrations ROT was also described to display off-target effects. Here we studied how ROT affected in vitro primary murine myotube formation. We demonstrate that myotube formation is specifically inhibited by ROT (10–100 nM), but not by piericidin A (PA; 100 nM), another CI inhibitor. At 100 nM, both ROT and PA fully blocked myoblast oxygen consumption. Knock-down of Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) and, to a lesser extent ROCK1, prevented the ROT-induced inhibition of myotube formation. Moreover, the latter was reversed by inhibiting Raf-1 activity. In contrast, ROT-induced inhibition of myotube formation was not prevented by knock-down of RhoA. Taken together, our results support a model in which ROT reduces primary myotube formation independent of its inhibitory effect on CI-driven mitochondrial ATP production, but via a mechanism primarily involving the Raf-1/ROCK2 pathway.
Original languageEnglish
Pages (from-to)1606-1614
JournalBiochimica et Biophysica Acta. C, Molecular Cell Research
Volume1853
Issue number7
DOIs
Publication statusPublished - 2015

Keywords

  • Rotenone
  • murine myotube formation
  • Raf-1
  • ROCK2

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