Six1 and Eya1 Expression Can Reprogram Adult Muscle from the Slow-Twitch Phenotype into the Fast-Twitch Phenotype

Abstract

Muscle fibers show great differences in their contractile and metabolic properties. This diversity enables skeletal muscles to fulfill and adapt to different tasks. In this report, we show that the Six/Eya pathway is implicated in the establishment and maintenance of the fast-twitch skeletal muscle phenotype. We demonstrate that the MEF3/Six DNA binding element present in the aldolase A pM promoter mediates the high level of activation of this promoter in fast-twitch glycolytic (but not in slow-twitch) muscle fibers. We also show that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 proteins accumulate preferentially in the nuclei of fast-twitch muscles. The forced expression of Six1 and Eya1 together in the slow-twitch soleus muscle induced a fiber-type transition characterized by the replacement of myosin heavy chain I and IIA isoforms by the faster IIB and/or IIX isoforms, the activation of fast-twitch fiber-specific genes, and a switch toward glycolytic metabolism. Collectively, these data identify Six1 and Eya1 as the first transcriptional complex that is able to reprogram adult slow-twitch oxidative fibers toward a fast-twitch glycolytic phenotype.

We thank D. Tuil for helpful discussions concerning electroporation, Sophie Gautron for critical reading of the manuscript, I. Hanson and G. Borsani for the gift of mouse Eya4 cDNA, C. Thornton for the gift of Six5 antibodies, A. Keller for the gift of enolase β antibodies, and Florence Bertin, Evelyne Souil, and Arlette Porteu for helpful technical assistance. We thank Fujisawa GmbH, Munich, Germany, for generously providing FK506.

R.G. and C.L. have been supported by a fellowship from the Ministere de la Recherche et de l'Education Nationale, and F.S. has been supported by a grant from the Société de Secours des Amis des Sciences. B.J.P. was supported by an Institut National pour la Santé et la Recherche Médicale (INSERM) travel fellowship. Financial support to this work has been provided by the INSERM, by an Action Concertée Incitative (ACI 0220514), and by the Association Française contre les Myopathies.