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Acta Neuropathol. 2008 Jun;115(6):663-74. doi: 10.1007/s00401-008-0371-5. Epub 2008 Mar 28.

Cyclosporin A modulates cellular localization of MEF2C protein and blocks fiber hypertrophy in the overloaded soleus muscle of mice.

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Health Science Center, Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi 441-8580, Japan.


The molecular signaling pathway linked to hypertrophy of the anti-gravity/postural soleus muscle after mechanical overloading has not been identified. Using reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemical analyses, we investigated whether the amounts of myocyte enhancer factor (MEF)2C, MEF2D, and myogenin change in the mechanically overloaded soleus muscle after treatment with the calcineurin inhibitor cyclosporine A (CsA). Adult male ICR mice were subjected to a surgical ablation of the gastrocnemius muscle and treated with either CsA (25 mg/kg) or vehicle, once daily. They were killed at 2, 4, 7, 10, and 14 days post-injury. Mechanical overloading resulted in a significant increase in the wet weight and the cross-sectional area of slow and fast fibers of the soleus muscle in placebo-treated mice but not CsA-treated mice. RT-PCR analysis did not show a marked difference in MEF2C and MEF2D mRNA levels in the overloaded soleus muscle in placebo- or CsA-administered mice. After 2 days of mechanical overloading, we observed co-localization of MEF2C and myogenin in several mononuclear cells under both conditions. These MEF2C-positive mononuclear cells also possessed immunoreactivity for c-Met, a satellite cell marker. At 4 days, mechanical overloading induced marked expression of MEF2C but not MEF2D in the subsarcolemmal region in a group of myotubes and/or myofibers. Such a MEF2C-positive region emerged less often in the hypertrophied soleus muscle subjected to the treatment with CsA. At 7 days, we observed many mononuclear cells possessing both MEF2C and myogenin protein in mice treated with CsA, but not the placebo. Our results demonstrated that CsA treatment modulates the amount and cellular localization of MEF2C protein. The modulation of MEF2C by CsA treatment may inhibit the hypertrophic process in the soleus muscle after mechanical overloading.

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