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

Hao Shi1, Jason M Scheffler, Jonathan M Pleitner

  • 1Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 18, 2008
PubMed

Insights

The extracellular signal-regulated kinase (ERK) 1/2 pathway preserves fast-twitch skeletal muscle fiber types. Inhibiting ERK signaling promotes a shift towards slower, more oxidative muscle fiber characteristics.

Area of Science:

  • Molecular Biology
  • Skeletal Muscle Physiology
  • Cell Signaling

Background:

  • Skeletal muscle exhibits diverse fiber types, crucial for varied physiological functions.
  • The molecular mechanisms driving skeletal muscle fiber type diversification are not fully understood.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein kinase (MAPK) signaling pathways in skeletal muscle fiber type determination.
  • To elucidate the specific involvement of extracellular signal-regulated kinase (ERK) 1/2 in maintaining fast-twitch muscle phenotypes.

Main Methods:

  • Utilized pharmacological inhibitors and genetic manipulations (overexpression) of ERK1/2, p38, and c-Jun NH2-terminal kinase (JNK) pathways.
  • Employed reporter gene assays and protein analysis (myosin heavy chain isoforms) in cultured myotubes and in vivo mouse/rat muscle models.
  • Investigated the effects of MAP kinase phosphatase-1 (MKP1) overexpression on fiber type conversion.

Main Results:

  • ERK1/2 pathway, unlike p38 or JNK, was preferentially activated in fast-twitch muscles.
  • Inhibition of ERK1/2 signaling in vitro and in cultured myotubes promoted slow-twitch fiber characteristics and repressed fast-twitch ones.
  • Overexpression of MKP1 in fast-twitch muscle fibers induced the synthesis of slower MyHC isoforms (IIa and I), indicating a shift towards a slow-twitch phenotype.
  • Forced MKP1 expression in vivo confirmed the conversion to slower fiber types, evidenced by reporter gene activity.
  • ERK2 activation upregulated the fast-twitch fiber program in the soleus muscle.

Conclusions:

  • The MAPK signaling cascade, particularly the ERK1/2 pathway, plays a critical role in maintaining the fast-twitch skeletal muscle fiber phenotype.
  • ERK1/2 signaling actively represses the slow-twitch fiber program, suggesting a key regulatory mechanism for fiber type specialization.

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