FOXO1 delays skeletal muscle regeneration and suppresses myoblast proliferation

• Published in: Bioscience, biotechnology, and biochemistry biotechnology, and biochemistry, 2016-08, Vol.80 (8), p.1531-1535
• Main Authors: Yamashita, Atsushi, Hatazawa, Yukino, Hirose, Yuma, Ono, Yusuke, Kamei, Yasutomi
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation; Cell Line; Cell Proliferation; Cobra Cardiotoxin Proteins - toxicity; Cyclin-Dependent Kinase Inhibitor p57 - genetics; Cyclin-Dependent Kinase Inhibitor p57 - metabolism; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; FOXO1; Gene Expression Regulation; Hindlimb Suspension; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Myoblasts - drug effects; Myoblasts - metabolism; Myoblasts - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Regeneration - genetics; skeletal muscle
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1080/09168451.2016.1164585

Unloading stress, such as bed rest, inhibits the regenerative potential of skeletal muscles; however, the underlying mechanisms remain largely unknown. FOXO1 expression, which induces the upregulated expression of the cell cycle inhibitors p57 and Gadd45α, is known to be increased in the skeletal muscle under unloading conditions. However, there is no report addressing FOXO1-induced inhibition of myoblast proliferation. Therefore, we induced muscle injury by cardiotoxin in transgenic mice overexpressing FOXO1 in the skeletal muscle (FOXO1-Tg mice) and observed regeneration delay in skeletal muscle mass and cross-sectional area in FOXO1-Tg mice. Increased p57 and Gadd45α mRNA levels, and decreased proliferation capacity were observed in C2C12 myoblasts expressing a tamoxifen-inducible active form of FOXO1. These results suggest that decreased proliferation capacity of myoblasts by FOXO1 disrupts skeletal muscle regeneration under FOXO1-increased conditions, such as unloading. FOXO1 upregulates the cell cycle inhibitors p57 and Gadd45α in myoblasts, which may contribute to the delay in skeletal muscle regeneration during unloading conditions.