Identification of the novel marker and drug target of sarcopenia

Aging related decline of muscle mass and strength (sarcopenia) is the leading cause for disability in aged population and a world pandemic. The development of efficient treatment for sarcopenia has been hampered by the lack of understanding about the onset mechanism of sarcopenia. Identification of the factors present in the circulation for sarcopenia diagnosis is a challenging task. No factors secreted by the skeletal muscle has been found to be able to regulate muscle mass.

Recently, HU Ping’s research groups from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (SIBCB, CAS)  identifies a novel circulating factor secreted by the aged skeletal muscle. This factor, named Dkk3, is a member of Dickkopf family and displays elevated protein levels in the circulating blood of sarcopenia patients. Dkk3 can serve as a new molecular diagnosis marker for sarcopenia. HU’s group further investigated the function of Dkk3 in sarcopenia and the underlying mechanism. Dkk3 can induce muscle atrophy by recruiting transcription factor FoxO3 and transcription co-activator β-catenin to the promoter of Fbxo32 and Trim63, which are muscle specific E3 ubiquitination ligases, to activate their transcription. The activation of Fbxo32 and Trim63 leads to massive degradation of muscle proteins and muscle atrophy. Overexpressing Dkk3 in young mice leads to significant decline of muscle mass and muscle functions, mimicking the muscle degeneration symptoms in sarcopenia patients. Reduction of Dkk3 level in sarcopenia mice improves muscle functions and increases muscle mass, suggesting that Dkk3 is a new therapeutic target for sarcopenia. This work reveals skeletal muscles as an important endocrine organ and identifies a new circuit driven by a few pieces of aged skeletal muscles to cause sarcopenia.  It provides new targets for diagnosis and treatment of sarcopenia. This study was published in Nature Communications.

This project received supports of the Chinese Academy of Sciences, Science and Technology Commission of Shanghai Municipality, and National Natural Science Foundation. Professor Lin Chen from Daping Hospital, The Third Military Medical University, and Professor Hongbin Ji from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences  (SIBCB, CAS)  helped the investigation.