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Modulation of skeletal muscle fiber type by mitogen-activated protein kinase signaling

Hao Shi^*, Jason M. Scheffler^*, Jonathan M. Pleitner^*, Caiyun Zeng^*, Sungkwon Park^*, Kevin M. Hannon, Alan L. Grant^* and David E. Gerrard^*,1

^* Department of Animal Sciences and

Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA

¹Correspondence: 915 W. State St., Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA. E-mail: dgerrard{at}purdue.edu

Skeletal muscle is composed of diverse fiber types, yet the underlying molecular mechanisms responsible for this diversification remain unclear. Herein, we report that the extracellular signal-regulated kinase (ERK) 1/2 pathway, but not p38 or c-Jun NH₂-terminal kinase (JNK), is preferentially activated in fast-twitch muscles. Pharmacological blocking of ERK1/2 pathway increased slow-twitch fiber type-specific reporter activity and repressed those associated with the fast-twitch fiber phenotype in vitro. Overexpression of a constitutively active ERK2 had an opposite effect. Inhibition of ERK signaling in cultured myotubes increased slow-twitch fiber-specific protein accumulation while repressing those characteristic of fast-twitch fibers. Overexpression of MAP kinase phosphatase-1 (MKP1) in mouse and rat muscle fibers containing almost exclusively type IIb or IIx fast myosin heavy chain (MyHC) isoforms induced de novo synthesis of the slower, more oxidative type IIa and I MyHCs in a time-dependent manner. Conversion to the slower phenotype was confirmed by up-regulation of slow reporter gene activity and down-regulation of fast reporter activities in response to forced MKP1 expression in vivo. In addition, activation of ERK2 signaling induced up-regulation of fast-twitch fiber program in soleus. These data suggest that the MAPK signaling, most likely the ERK1/2 pathway, is necessary to preserve the fast-twitch fiber phenotype with a concomitant repression of slow-twitch fiber program.—Shi, H., Scheffler, J. M., Pleitner, J. M., Zeng, C., Park, S., Hannon, K. M., Grant, A. L., Gerrard, D. E. Modulation of skeletal muscle fiber type by mitogen-activated protein kinase signaling.

Key Words: ERK1/2 • MKP-1 • plasticity • signal transduction