Following skeletal muscle injury, muscle stem cells (satellite cells) are activated, proliferate, and differentiate to form myofibers. We show that mRNA-decay protein AUF1 regulates satellite cell function through targeted degradation of specific mRNAs containing 3′ AU-rich elements (AREs). auf1−/− mice undergo accelerated skeletal muscle wasting with age and impaired skeletal muscle repair following injury. Satellite cell mRNA analysis and regeneration studies demonstrate that auf1−/− satellite cell self-renewal is impaired due to increased stability and overexpression of ARE-mRNAs, including cell-autonomous overexpression of matrix metalloprotease MMP9. Secreted MMP9 degrades the skeletal muscle matrix, preventing satellite-cell-mediated regeneration and return to quiescence. Blocking MMP9 activity in auf1−/− mice restores skeletal muscle repair and maintenance of the satellite cell population. Control of ARE-mRNA decay by AUF1 represents a mechanism for adult stem cell regulation and is implicated in human skeletal muscle wasting diseases.
Bibliographical noteFunding Information:
We thank Dr. Bruce Cronstein (NYU) for use of the DEXA. Technical assistance was provided by the NYU-CTSI Bioinformatics Core, Histopathology Core, Microscopy Core, Rodent Behavior Core, and Small Animal Imaging Core, supported in part by grant UL1 TR00038 from NCATS. This work was supported by NIH grants GM085693 and R24OD018339 to R.J.S., NIH T32 13-A0-S1-090476 to D.M.C., and AR049446 to B.B.O., who is also supported as a Senior Scholar in Aging Research by the Ellison Medical Foundation.
© 2016 The Authors
- AU-rich elements
- mRNA decay
- muscle regeneration
- muscle stem cells
- satellite cells