Journal Article

Identification of a KLF5-dependent program and drug development for skeletal muscle atrophy

Nakashima, Tomoki, Koike, Hiroyuki, Manabe, Ichiro, Ono, Takehito, Hayashi, Shinichiro, Oishi, Yumiko, Kaneda, Atsushi, Kudo, Fujimi, Liu, Lin, Kagechika, Hiroyuki

2021

Overview

Skeletal muscle atrophy is caused by various conditions, including aging, disuse related to a sedentary lifestyle and lack of physical activity, and cachexia. Our insufficient understanding of the molecular mechanism underlying muscle atrophy limits the targets for the development of effective pharmacologic treatments and preventions. Here, we identified Krüppel-like factor 5 (KLF5), a zinc-finger transcription factor, as a key mediator of the early muscle atrophy program. KLF5 was up-regulated in atrophying myotubes as an early response to dexamethasone or simulated microgravity in vitro. Skeletal muscle–selective deletion of Klf5 significantly attenuated muscle atrophy induced by mechanical unloading in mice. Transcriptome- and genome-wide chromatin accessibility analyses revealed that KLF5 regulates atrophy-related programs, including metabolic changes and E3-ubiquitin ligase-mediated proteolysis, in coordination with Foxo1. The synthetic retinoic acid receptor agonist Am80, a KLF5 inhibitor, suppressed both dexamethasone- and microgravity-induced muscle atrophy in vitro and oral Am80 ameliorated disuse– and dexamethasone-induced atrophy in mice. Moreover, in three independent sets of transcriptomic data from human skeletal muscle, KLF5 expression significantly increased with age and the presence of sarcopenia and correlated positively with the expression of the atrophy-related ubiquitin ligase genes FBXO32 and TRIM63. These findings demonstrate that KLF5 is a key transcriptional regulator mediating muscle atrophy and that pharmacological intervention with Am80 is a potentially preventive treatment.

• Publisher: National Academy of Sciences
• Subject: Aging / Animals / Atrophy / Benzoates - pharmacology / Biological Sciences / Cachexia / Chromatin / Dexamethasone / Dexamethasone - toxicity / Drug Development / FOXO1 protein / Gene Expression Regulation - drug effects / Genomes / Glucocorticoids - toxicity / Kruppel-Like Transcription Factors - physiology / Male / Mechanical unloading / Medical Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Microgravity / Muscle Proteins - genetics / Muscle Proteins - metabolism / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscles / Muscular Atrophy - chemically induced / Muscular Atrophy - drug therapy / Muscular Atrophy - metabolism / Muscular Atrophy - pathology / Musculoskeletal system / Myotubes / Pharmacology / Physical activity / Proteolysis / Retinoic acid / Sarcopenia / Signal Transduction / Skeletal muscle / SKP Cullin F-Box Protein Ligases - genetics / SKP Cullin F-Box Protein Ligases - metabolism / Tetrahydronaphthalenes - pharmacology / Transcriptomes / Tripartite Motif Proteins - genetics / Tripartite Motif Proteins - metabolism / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Zinc finger proteins