Icaritin requires Phosphatidylinositol 3 kinase (PI3K)/Akt signaling to counteract skeletal muscle atrophy following mechanical unloading.

Zong-Kang Zhang,Jin Liu,Albert Leung,Bao-Ting Zhang,Baosheng Guo,Jie Li,Ge Zhang

doi:10.1038/srep20300

Abstract

Counteracting muscle atrophy induced by mechanical unloading/inactivity is of great clinical need and challenge. A therapeutic agent that could counteract muscle atrophy following mechanical unloading in safety is desired. This study showed that natural product Icaritin (ICT) could increase the phosphorylation level of Phosphatidylinositol 3 kinase (PI3K) at p110 catalytic subunit and promote PI3K/Akt signaling markers in C2C12 cells. This study further showed that the high dose ICT treatment could significantly attenuate the decreases in the phosphorylation level of PI3K at p110 catalytic subunit and its downstream markers related to protein synthesis, and inhibit the increases in protein degradation markers at mRNA and protein levels in rat soleus muscle following 28-day hindlimb unloading. In addition, the decreases in soleus muscle mass, muscle fiber cross-sectional area, twitch force, specific force, contraction time and half relaxation time could be significantly attenuated by the high dose ICT treatment. The low dose ICT treatment could moderately attenuate the above changes induced by unloading. Wortmannin, a specific inhibitor of PI3K at p110 catalytic subunit, could abolish the above effects of ICT in vitro and in vivo, indicating that PI3K/Akt signaling could be required by ICT to counteract skeletal muscle atrophy following mechanical unloading.

Highlights

Skeletal muscles respond to the stimulus of mechanical load for growth and maintenance
The current study is the first one to demonstrate that ICT could require Phosphatidylinositol 3 kinase (PI3K)/Akt signaling to attenuate the skeletal muscle atrophy induced by mechanical unloading in a dose-dependent manner in adult rats
The high dose ICT treated animals showed 25.4% higher in muscle mass and 48.1% higher in muscle fiber cross-sectional area (CSA) compared to the hindlimb suspension (HS) animals, the low dose ICT treatment showed moderate attenuation effect

Summary

Introduction

Skeletal muscles respond to the stimulus of mechanical load for growth and maintenance. Administration of LY294002 or wortmannin, specific inhibitors of PI3K, could significantly inhibit the effect of ICT or icariin treatment[27,28,29,30,31], suggesting that PI3K/Akt signaling pathway might be involved in various biological effects of ICT. These clues inspire a hypothesis that ICT could require PI3K/Akt signaling pathway to counteract skeletal muscle atrophy induced by mechanical unloading. We investigated the effect of ICT with or without PI3K inhibitor on protein synthesis/ degradation, PI3K/Akt signaling pathway, muscle type distribution, histomorphology and mechanical function in skeletal muscles during mechanical unloading

Methods

Results

Conclusion