Screening of compounds regulating FOXO1 transcriptional activity

Skeletal muscle is the largest organ in the human body, and plays a critical role in energy expenditure, glucose metabolism, and exercise. The mass and composition of skeletal muscle affect its function, and changed by physical activity, the environment, and disease. For example, malnutrition and inactivity, such as aging, bed rest, and plaster casts, cause muscle atrophy. FOXO1, a member of the forkhead‐type transcriptional factors, is up‐regulated during muscle atrophy. FOXO1 enhances expression of genes involved in protein degradation by the ubiquitin‐proteasome system and autophagy. In fact, we have shown that transgenic mice specifically overexpressing FOXO1 in skeletal muscles exhibited muscle atrophy. Also, deletion of FOXO1 inhibited expression of enzymes involved in protein degradation induced during muscle atrophy. Namely, FOXO1 is a key regulator of muscle atrophy. Thus, we attempt to search for compounds that inhibit FOXO1 transcriptional activity. We establish a system to evaluate FOXO1 transcriptional activity by using FOXO1 conjugated with the GAL4‐DNA binding domain. Indeed, luciferase reporter expression was induced by FOXO1. Using this reporter system, we screened compounds in terms of their ability to inhibit the FOXO1 pathway. In this study, we found several compounds attenuated luciferase activity in 400 biologically active substances from natural products and plants. These compounds likely inhibit FOXO1 transcriptional activity and may attenuate muscle atrophy.