Grefte 2015 Biochim Biophys Acta

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Grefte S, Wagenaars JA, Jansen R, Willems PH, Koopman WJ (2015) Rotenone inhibits primary murine myotube formation via Raf-1 and ROCK2. Biochim Biophys Acta 1853:1606-14.

» PMID: 25827955

Grefte S, Wagenaars JA, Jansen R, Willems PH, Koopman WJ (2015) Biochim Biophys Acta

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.

Keywords: Fusion index, GW5074, U0126, Rotenone, Piericidin A, Rho-GTPase

O2k-Network Lab: NL Nijmegen Koopman WJ

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Skeletal muscle, Other cell lines  Preparation: Intact cells 

Regulation: Inhibitor  Coupling state: ROUTINE 

HRR: Oxygraph-2k