ABSTRACT
Muscle atrophy due to fragility fractures or frailty worsens not only activity of daily living and healthy life expectancy, but decreases life expectancy. Although several therapeutic agents for muscle atrophy have been investigated, none is yet in clinical use. Here we report that bezafibrate, a drug used to treat hyperlipidemia, can reduce immobilization-induced muscle atrophy in mice. Specifically, we used a drug repositioning approach to screen 144 drugs already utilized clinically for their ability to inhibit serum starvation-induced elevation of Atrogin-1, a factor related to muscle atrophy, in myotubes in vitro. Two candidates were selected, and here we demonstrate that one of them, bezafibrate, significantly reduced muscle atrophy in an in vivo model of muscle atrophy induced by leg immobilization. In gastrocnemius muscle, immobilization reduced muscle weight by an average of ~ 17.2%, and bezafibrate treatment prevented ~ 40.5% of that atrophy. In vitro, bezafibrate significantly inhibited expression of the inflammatory cytokine Tnfa in lipopolysaccharide-stimulated RAW264.7 cells, a murine macrophage line. Finally, we show that expression of Tnfa and IL-1b is induced in gastrocnemius muscle in the leg immobilization model, an activity significantly antagonized by bezafibrate administration in vivo. We conclude that bezafibrate could serve as a therapeutic agent for immobilization-induced muscle atrophy.
