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

Abstract

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 NH(2)-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.

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

“…FAK activity is required for efficient myotube formation during muscle regeneration in response to injury, in fusion and costamere development of primary mouse myoblasts, and in survival of proliferating C2C12 myoblasts and their differentiation into myotubes (Clemente et al, 2005;Quach and Rando, 2006;Quach et al, 2009). ERK activity has both positive and negative roles in C2C12 cell differentiation (Wu et al, 2000;Li and Johnson, 2006;Cho et al, 2007;Yokoyama et al, 2007); it is also implicated in fiber type identity in vivo (Murgia et al, 2000;Shi et al, 2008). The ERK substrate p90RSK has also been implicated in C2C12 cell differentiation (Cho et al, 2007).…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…Consistently, reduced levels of active ERK were reported in sarcopenia of aging (Carlson et al, 2009). ERK inhibition seems required to increase ubiquitin ligase expression in cultured murine myocytes (Shi et al, 2008). By contrast, in the same model system, ERK activation results in reduced myotube size (Rommel et al, 1999), while its inhibition leads to a hypertrophic phenotype (Rommel et al, 1999).…”

“…Its inactivation in experimental animals results in muscle atrophy (Shi et al, 2009). Not only, it appears able to counteract the anabolic stimuli induced by treatment with  2 -adrenergic agonists or IGF-1 (Haddad & Adams, 2004;Shi et al, 2007).…”

Mitogen-Activated Protein Kinases and Mitogen-Activated Protein Kinase Phosphatases in Regenerative Myogenesis and Muscular Dystrophy

“…MKP-1 is also implicated in adult skeletal muscle fiber specialization (Shi et al, 2008). Overexpression of MKP-1 in adult type IIb (glycolytic) myofibers converts these fibers to slower-twitch type IIa or type I (oxidative) fibers, suggesting that MKP-1-mediated dephosphorylation of MAPK signaling is required to maintain the glycolytic fiber phenotype through the repression of slow myofibers (Shi et al, 2008).…”

“…Overexpression of MKP-1 in adult type IIb (glycolytic) myofibers converts these fibers to slower-twitch type IIa or type I (oxidative) fibers, suggesting that MKP-1-mediated dephosphorylation of MAPK signaling is required to maintain the glycolytic fiber phenotype through the repression of slow myofibers (Shi et al, 2008). Consistent with these data, it has been shown that MKP-1-deficient mice are protected from the loss of oxidative myofibers during high fat diet-induced obesity (Roth et al, 2009).…”