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

Abstract

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 diseases 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 in MuSC/MPC function. Methods Primary human MPCs ( h MPCs) were used for in vitro experiments, and young (4–6 mo) and old (>20 mo) mice were used for in vivo experiments. 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 h MPC 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 h MPCs 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 h MPCs resulted in cell cycle arrest in G0/G1. Extracellular serine/glycine was necessary to support glutathione and global protein synthesis in h MPCs. Using an aged mouse model, we found that reduced serine/glycine availability augmented intermyocellular adipocytes 28 days post-injury. Conclusions These studies demonstrated that despite an absolute serine/glycine requirement for MuSC/MPC proliferation, de novo synthesis was inadequate to support these demands, making extracellular serine and glycine conditionally essential for efficient skeletal muscle regeneration.

NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions

“…Plasma samples from healthy fasted adults (29-42 years, 5 male, 3 female) were obtained from a clinical cohort recruited from Tompkins County, New York area as described previously (Gheller et al, 2021).…”

Subchronic Tolerance Trials of Graded Oral Supplementation with Phenylalanine or Serine in Healthy Adults

“…In the case of serine, peer-reviewed supplementation studies that would aid in discussing the current results within a broader perspective are missing. This may soon change due to recent findings of decreased serine levels in both the blood circulation and skeletal muscle with aging and disease [7].…”

“…Phenylalanine is a precursor of tyrosine and catecholaminergic neurotransmitters [6]. Recent peer-reviewed research with supplemental serine includes nutritional support of skeletal muscle regeneration [7] and treatment of amyotrophic lateral sclerosis [8]. Phenylalanine, being one of the nine essential amino acids, is regularly added to essential amino acid mixes that are used in an array of products, ranging from sport supplements intended for athletes [9] to foods and/or supplements addressing sarcopenia in elderly persons [10].…”

Importance of Nutrient Availability and Metabolism for Skeletal Muscle Regeneration

“…One tracing study, using 13 C labeled glucose, identified that glucose contributes to histone acetylation in proliferating MPCs (Yucel et al, 2019). Another study demonstrated, using 13 C glucose, that glucose contributes minimally to the synthesis of the non-essential amino acids, serine and glycine, in proliferating MPCs; however, the contribution of glucose to serine or glycine is not sufficient to maintain proliferation in the absence of extracellular serine and glycine (Gheller et al, 2020). The necessity of glucose for other biosynthetic pathways has received limited attention.…”

“…Follow-up research has identified specific factors in circulation, such as nutrients, that are essential for muscle tissue regeneration. For example, our lab demonstrated that the NEAA L-serine and the closely related NEAA L-glycine are required from an extracellular source for human MPC proliferation in cell culture models (Gheller et al, 2020). Additionally, a diet deficient in L-serine and glycine impaired recovery from myotoxin-induced muscle injury by reducing the number of MPCs and inducing intramuscular fat infiltration in aged animals (Gheller et al, 2020).…”