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Researchers here identify a mechanism by which the practice of calorie restriction promotes muscle stem cell function, and thus repair and maintenance of muscle tissue. In animal studies calorie restriction is shown to produce both (a) a short-term effect associated with improved regeneration, and (b) a long-term effect in the sense of slowing the progressive loss of muscle mass and strength leading to sarcopenia. The research community will no doubt build on the findings here to suggest pharmaceutical approaches to mimic this aspect of calorie restriction.
Using an unbiased proteomics approach, we report here that calorie restriction (CR) promotes a hypersecretion of proteins from the liver, including those involved in coagulation and fibrinolysis. We also demonstrated the role of liver-derived plasminogen in mediating satellite cell expansion and enhanced muscle regeneration during CR. We showed that the mediation was accomplished by an upregulation of the plasminogen receptor Plg-RKT specifically on muscle satellite cells, promoting downstream ERK signaling and subsequent proliferation. We therefore propose that CR induces a distinct crosstalk between liver and muscle that increases muscle resilience.
Using the MetRSL274G/bio-orthogonal non-canonical amino acid tagging (BONCAT) model to characterize an organ-specific secretome in vivo, our study aimed to investigate the systemic and extracellular effects of CR and how this could alter tissue resilience. We chose to investigate metabolic tissues with known effects of CR, including liver, skeletal muscle, and adipose tissue. We were intrigued by the induction of secreted proteins from the liver with CR, which was not evident in proteins secreted by either adipose or muscle tissues. The induction of the secretome was observed just 2 weeks after CR and continued throughout the 3-month CR period.
Interestingly, CR increased secretion of proteins associated with the resolution of both coagulation and hemostasis. Although not the focus of this paper, these findings suggest increased secretion of fibrinolytic factors from the liver as a possible mechanism to improve cardiovascular health with CR, given that elevated hemostatic factor levels are typically associated with worsened clinical cardiovascular outcomes, such as increased risk of cardiovascular death. Conversely, CR dampened secretion of proteins associated with increased inflammation, which is consistent with known anti-inflammatory effects of CR and further validates our proteomics approach.
To demonstrate the relevance of our findings to human biology, we analyzed tissues from the CALERIE trial of human CR. We observed replication of many of the mouse phenotypes, including increased circulating plasminogen, decreased PAI-1, satellite cell expansion, and increased Plg-RKT expression on the satellite cells of human CALERIE study participants. This study also reports the expansion of satellite cells in human muscle with CR. This finding is critical to suggest translational relevance to the rodent data observed for more than a decade. Moreover, the increased expression of the plasminogen receptor Plg-RKT observed on human satellite cells during CR provided additional support for the theory that our rodent model is relevant to human biology.
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