TLE4 regulates muscle stem cell quiescence and differentiation.

Our skeletal muscle has an extraordinary capability to regenerate following muscle damage due to injury or disease. A muscle resident pool of stem cells known as satellite cells are essential for skeletal muscle regeneration. Under normal conditions (homeostasis), the satellite cells remain largely dormant (quiescent), but get activated upon muscle injury, leading them to divide to increase in numbers, followed by differentiation to repair and regenerate the damaged muscle fibers. Muscle stem cells express a transcription factor whose expression is crucial for satellite cell function called Pax7, which activates the expression of Myf5, a myogenic regulatory factor essential for initiating differentiation of satellite cells. A key question in the field is how Pax7-mediated Myf5 activation is prevented under homeostasis when the satellite cells are quiescent, and how Myf5 is activated by Pax7 during muscle injury.
In this study, we identify a novel molecular mechanism by which Pax7-mediated Myf5 regulation is controlled. We find that the corepressor Transducin-like Enhancer of Split 4 (TLE4) is a novel Pax7 interacting protein, which occupies the Myf5 enhancer along with Pax7 to prevent Myf5 activation under homeostasis. Upon muscle injury, TLE4 expression is transiently downregulated, permitting Pax7-mediated Myf5 activation and consequent differentiation of satellite cells to regenerate damaged muscle fibers. In experiments where knockdown of TLE4 was performed, we observed premature Myf5 expression, earlier onset of differentiation and impaired regeneration. Thus, our study identifies TLE4 as a crucial regulator of satellite cell quiescence, which could be an important regulatory mechanism of relevance to other stem cell systems. Our results on TLE4 regulating muscle stem cell quiescence and differentiation should be of interest in muscle regeneration following injury and in muscle diseases such as Duchenne muscular dystrophy.

Agarwal, M*., Bharadwaj, A*., and Mathew, S. J. (2022). TLE4 regulates muscle stem cell quiescence and skeletal muscle differentiation. Journal of Cell Science 135(4), jcs256008. doi:10.1242/jcs.256008 (Article featured on the journal cover).
https://doi.org/10.1242/jcs.256008

Image legend:
Myoblast cells were isolated from wild type mice at postnatal day 0, cultured, treated with a control siRNA, and allowed to differentiate for 5 days. This is an immunofluorescence image of such a culture, labeled using a mixture of myosin heavy chain antibodies (Red), phalloidin (Green) and DAPI (Blue). In addition to the differentiated myofibers which express myosin heavy chain (Red), undifferentiated myoblasts and non-muscle cells, whose nuclei are labeled by DAPI (Blue) can also be seen.