Vertebrates can only move and breathe with the help of their skeletal muscles, which play a significant role in warmth creation and the body’s metabolism. In order to perform these functions, the organism has to be able to repair torn muscles quickly and efficiently. A research team led by Prof. Dr. Roland Schüle and Milica Tosic has now proven that the epigenetic enzyme lysine-specific demethylase (Lsd1) plays a key role in the regeneration of skeletal muscle and in the early stages of development of the responsible satellite cells, a special type of stem cell. The researchers recently published their findings in the journal Nature Communications.
Satellite cells sit beneath the so-called basement membrane, which encases the muscle cells, and have the ability to develop into muscle cells as well as into brown fat cells. Up to now, however, the molecular mechanisms that regulate the process have not been entirely known.
The Freiburg team injected genetically modified mice with snake venom, thereby causing injury to their muscles. It showed that an increased Lsd1 level accelerates the development into muscle cells because the enzyme triggers the expression – that is, gene regulation and protein transcription – that promote muscle formation and regeneration. In contrast, a lack of Lsd1 or inhibition of its activity resulted in delayed regeneration. The enzyme’s removal also caused the satellite cells to turn into fat cells instead of muscle cells. These cells not only produce the protein perilipin 1, but also the protein Ucp1, which occurs exclusively in brown fat cells. In order to prove that these are actually formed from satellite cells, the scientists tagged the stem cells with a green fluorescent protein and were thus able to track the formation of brown fat cells during the regeneration process.
At the molecular level, the researchers showed that Lsd1 prevents the development of satellite cells to brown fat cells by inhibiting the protein GLIS family zinc finger 1 (Glis1). In contrast, elevated levels of Glis1 in mice and in in vitro experiments were sufficient to promote differentiation into brown adipocytes, thus mimicking the effect of Lsd1 removal. In summary, the studies have shown that suppression of Glis1 and concomitant up-regulation of Lsd1 ensure muscle recovery.
Roland Schüle and Milica Tosic conduct their research in the Department of Urology and in the Clinical Research Center at the Medical Center – University of Freiburg. In addition, Schüle is a member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies.
Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells.
Tosic M, Allen A, Willmann D, Kim J, Lepper C, Duteil D, Schüle R.
NatComm. 2017, DOI: 10.1038/s41467-017-02740-5
Report about Roland Schüle’s research in uniˈwissen (only in German):