Posted by Friends of FSH Research on Dec 9, 2019
Update by Sachiko Homma, PhD
See grant Mechanisms of DUX4-induced muscle atrophy
Institution: Boston University School of Medicine, Department of Neurology
Muscle mass and size generally reflect the balance between protein synthesis and degradation in the muscle tissues. Muscle atrophy is characterized by small muscle mass and thin myofibers, which is the result of loss of proteins due to more protein degradation than synthesis. The ubiquitin-proteasome system (UPS) is responsible for degrading the great majority (at least 80%) of total proteins including many regulated, short-lived, abnormal, denatured, or, in general, damaged proteins. The UPS has been shown to play an important role in mediating muscle atrophy. The expression of DUX4, a causable gene for FSHD, has been shown to change the expression of many genes that are involved in the UPS. Despite the potential importance of this pathway in FSHD pathology, to my knowledge, little has been studied about proteasome regulation in FSHD muscles. In this study, we found that DUX4 expression in cultured myogenic cells induced newly identified protein which could lead to muscle atrophy (called ZFAND5). ZFAND5 can bind to both ubiquitinated proteins and proteasomes directly, therefore markedly enhancing cell’s capacity of protein degradation. In addition to ZFAND5, DUX4 induced expression of subunits of the proteasome, as well as increased the amount of assembled proteasomes and enhanced proteasome activity. These changes were observed not only in cultured myogenic cells, but also DUX4-expressing muscle tissues from an FSHD mouse model. In conclusion, our results show a possible association of ZFAND5 and DUX4, and a potential mechanism for the excessive proteolysis may be a result of the additive effects from (1) DUX4 increasing proteasome expression and (2) ZFAND5 activating the proteasomes. We are continuing to identifying new potential therapeutic targets that can inhibit the excessive proteolysis induced by DUX4.