Cedrol derivative attenuates muscle atrophy through regulation of myostatin transcription via Ca²⁺-CaMK-FoxO3a signaling pathways

Sarcopenia is a progressive and generalized muscle wasting syndrome characterized by loss of muscle strength and mass. Although many drug candidates have been developed to treat sarcopenia, their results were unsuccessful due to adverse or off-target effects. In this study, we identified a cedrol derivative which is a bioactive sesquiterpene having substantial suppressive effects on muscle atrophy. We demonstrated that the cedrol analog regulated myostatin expression via transcriptional regulation and that the cedrol derivative regulated this expression more effectively than the original form. Cedrol derivative stimulated Ca²⁺ via the mouse olfactory receptor 23 (MOR23) and induced interactions between phospho-CaMKII and FoxO3a in a calcium-dependent manner. In animal models, the transcript-level expressions of myostatin and MuRF1 were lower in the extensor digitorum longus (EDL) and soleus muscles of mice fed with cedrol-derivative diet. These findings reveal that cedrol derivative suppresses sarcopenia by inhibiting myostatin and MuRF1 expressions in both in vitro and in vivo models, thus suggesting that cedrol derivatives can be potential therapeutic agents for sarcopenia.