Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy
Lin Liu, Hiroyuki Koike, T. Ono, Shinichiro Hayashi, Fujimi Kudo, Atsushi Kaneda, Hiroyuki Kagechika, Ichiro Manabe, Tomoki Nakashima, Yumiko Oishi
Abstract
Significance Skeletal muscle atrophy occurs as a result of a variety of conditions including aging, disuse, and cachexia. In this study, we show that the transcription factor KLF5 is transiently up-regulated by metabolic and disuse stimulations and plays a pivotal role in the onset of muscle atrophy in vitro and in vivo. KLF5 physically interacts with Foxo1, and together, they regulate the transcription of Fbxo32 , a key atrophy-inducing ubiquitin ligase. A synthetic retinoid, Am80, attenuates muscle atrophy in vitro and in vivo. Moreover, publicly available data sets showed that in humans, KLF5 expression significantly increased with aging and with sarcopenia and correlated positively with expression of the ubiquitin ligase genes FBXO32 and TRIM63 .