Extracellular serine and glycine are required for mouse and human skeletal muscle stem and progenitor cell function

Brandon J. Gheller, Jamie E. Blum, Esther W. Lim, Michal K. Handzlik, ... Anna E. Thalacker-Mercer

Objective

Skeletal muscle regeneration relies on muscle-specific, adult stem cells (MuSCs), MuSC progeny, muscle progenitor cells (MPCs), and a coordinated myogenic program that is influenced by the extracellular environment. Following injury, MPCs undergo a transient and rapid period of population expansion, which is necessary to repair damaged myofibers and restore muscle homeostasis. Certain pathologies (e.g., metabolic disease and muscle dystrophies) and advanced age are associated with dysregulated muscle regeneration. The availability of serine and glycine, two nutritionally, non-essential amino acids, is altered in humans with these pathologies and these amino acids have been shown to influence the proliferative state of non-muscle cells. Our objective was to determine the role of serine/glycine on MuSC/MPC function.

Methods

For in vitro experiments, primary, human MPCs (hMPCs) were used and for in vivoexperiments young (4-6 mo) and old (>20 mo) mice were used. Serine/glycine availability was manipulated using specially formulated media in vitro or dietary restriction in vivo followed by downstream metabolic and cell proliferation analyses.

Results

We identified that serine/glycine are essential for hMPC proliferation. Dietary restriction of serine/glycine, in a mouse model of skeletal muscle regeneration, lowered the abundance of MuSCs 3 days post injury. Stable-isotope tracing studies showed that hMPCs rely on extracellular serine/glycine for population expansion because they exhibit a limited capacity for de novo serine/glycine biosynthesis. Restriction of serine/glycine to hMPCs resulted in cell cycle arrest in G0/G1. Extracellular serine/glycine were necessary to support glutathione and global protein synthesis in hMPCs. Finally, using an aged mouse model we find that reduced serine/glycine availability augmented intermyocellular adipocytes 28 days post injury.

Conclusions

These studies demonstrate that despite an absolute requirement of serine/glycine for MuSC/MPC proliferation, de novo synthesis is inadequate to support these demands making extracellular serine and glycine conditionally essential for efficient skeletal muscle regeneration.