Tier 3 — preclinical

Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration

Ciuffoli V, Feng X, Jiang K, Acevedo-Luna N, Ko KD, Wang AHJ, Riparini G, Khateb M, Glancy B, Dell'Orso S, Sartorelli V
Genes & Development 2024 38(3-4):151-167

Bibliography

PubMed
PMID 38453480
PubMed Central
PMC10982694
DOI
10.1101/gad.351428.123
Funding
Supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, grants AR041126 and AR041164 to Vittorio Sartorelli. Aged mice were provided by the National Institute on Aging.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignMechanistic muscle stem-cell study with genetic perturbation, metabolomics and mouse regeneration experiments.
ModelMouse muscle stem cells, conditional Psat1-deficient mice and old mice.
SampleMultiple cell and mouse cohorts across mechanistic and regeneration experiments.
InterventionGenetic Psat1 manipulation plus alpha-ketoglutarate or glutamine rescue in adult and old mice.
DurationAcute muscle-injury and regeneration time courses.
EndpointsMuscle stem-cell activation; Myogenic progenitor expansion; Muscle regeneration; AKG levels; Glutamine metabolism

What the study showed, in plain terms

This NIH-led study identified AKG as part of the metabolic machinery that allows muscle stem cells to activate and regenerate tissue.

Psat1, AKG and glutamine were lower in muscle stem cells from old mice. Providing AKG or glutamine rescued defective regeneration in relevant genetic and aged-mouse models.

This is strong muscle-aging biology, but it does not establish that an oral Ca-AKG supplement prevents sarcopenia in people.

Key findings

  • Psat1 supported muscle stem-cell activation through production of AKG and AKG-derived glutamine.
  • AKG was lower in muscle stem cells from old mice.
  • AKG or glutamine restored aspects of muscle regeneration in old or Psat1-deficient mice.

What this study can and cannot tell us

  • Preclinical mouse and stem-cell evidence.
  • The rescue experiments do not reproduce the pharmacology of oral Ca-AKG supplementation.
  • No human muscle-performance or sarcopenia outcomes were measured.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology