Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT

• Published in: Cell reports (Cambridge) Vol. 43; no. 3; p. 113881
• Main Authors: Bareja, Akshay, Lee, David E., Ho, Tricia, Waitt, Greg, McKay, Lauren H., Hannou, Sarah A., Orenduff, Melissa C., McGreevy, Kristen M., Binder, Alexandra, Ryan, Calen P., Soderblom, Erik J., Belsky, Daniel W., Ferrucci, Luigi, Das, Jayanta Kumar, Banskota, Nirad, Kraus, Virginia B., Huebner, Janet L., Kraus, William E., Huffman, Kim M., Baht, Gurpreet S., Horvath, Steve, Parmer, Robert J., Miles, Lindsey A., White, James P.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 26.03.2024; Elsevier
• Subjects: CALERIE; caloric restriction; CP: Metabolism; CP: Stem cell research; liver; MetRS; muscle; PAI-1; plasminogen; satellite cell; secretome; stem cell; plasminogen; MetRS; caloric restriction; satellite cell; CP: Stem cell research; stem cell; liver; CP: Metabolism; muscle; PAI-1; CALERIE; secretome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113881

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR. [Display omitted] •Short-term caloric restriction (CR) drastically alters the liver-derived plasma proteome•Circulating plasminogen increases with CR, which is necessary for satellite cell expansion•During CR, plasminogen signals to the satellite cell via the plasminogen receptor Plg-RKT•Loss of Plg-RKT prevents CR-induced SC expansion and associated regenerative enhancements Short-term caloric restriction (CR) has been shown to expand the muscle satellite cell pool and accelerate the early phase of muscle regeneration. Bareja et al. report robust changes in the liver-derived plasma proteome during CR and identify plasminogen as a contributing factor to the satellite cell expansion, signaling through Plg-RKT.