Losing muscle strength is a natural part of aging. At the core of this decline is a drop in the number of muscle stem cells (MuSCs), the specialized cells responsible for maintaining and regenerating muscle tissue throughout our lives. Loss of muscle strength can severely affect mobility, increasing the risk of falls, fractures and, most importantly, the loss of independence.
Published in Nature Aging, a recent study took a crucial first step toward restoring stem cell function in aging muscles—gaining a clearer understanding of how metabolism changes when stem cells are activated and how these critical processes weaken with age.
The researchers’ investigation led them to glutamine metabolism, the process by which cells use the amino acid glutamine to support essential functions. They found that for MuSCs, glutamine is more than just a nutrient. It provides the raw material needed to produce fatty acids that help cells grow, divide, and repair damaged muscles.
Aged MuSCs have about 50% less of a protein called glutaminase (GLS1), a protein that helps with glutamine usage. Without enough GLS1, muscle stem cells struggle to use glutamine effectively, resulting in impaired growth and damage repair.
When the missing protein was genetically restored, the older cells seemed to wake up again, regaining their ability to grow and regenerate larger, stronger muscles.
Tracing the metabolic trail
Muscle stem cells are crucial to muscle health. These satellite cells do the handywork of repairing damaged muscles by giving them new cell nuclei after an injury or strain. Newer studies have shown that they take their maintenance responsibilities seriously even without an injury.
When MuSCs become active, they undergo major changes in both their structure and their energy production. They build more mitochondria and increase glycolysis, a process that quickly generates energy from glucose. Even with these energy-boosting changes, the cells may still struggle to produce enough energy during the intense period of activation.
Many stem cells use glutamine metabolism to support energy production and to provide the building blocks needed for the synthesis of other amino acids and nucleic acids.
The researchers in this study were curious whether glutamine was the missing component that provided the extra energy boost when required.
Their first step was to compare the muscles of young and old mice using a specialized technique called fluorescence-activated cell sorting (FACS), which allowed them to accurately identify and isolate muscle stem cells from the muscle tissue. They also used stable isotope tracing to track how the cells processed glutamine.
They found that aging MuSCs show a marked decline in glutaminase (GLS) activity. Healthy young stem cells channeled glutamine through a specific reverse metabolic pathway (reductive TCA cycle) supported by the mitochondrial enzyme IDH2, to produce fatty acids—the essential building blocks needed for muscle growth and repair.
In older muscle stem cells, however, levels of the GLS1 (glutaminase) protein were reduced by half, which significantly slows the repair process due to a shortage of these essential fatty acids.
To further test this, the researchers genetically modified muscle stem cells so that deletion of the Gls1 gene could be specifically activated by a drug. With the gene absent, the usual increase in active stem cells after muscle injury was significantly impaired.
On the brighter side, the team discovered that old MuSCs could actually be re-energized—either by genetically restoring the GLS1 protein or by directly supplying the missing fatty acids. After these boosted stem cells were introduced into older mice, the animals developed muscle fibers that were about 45% larger and showed clear improvements in movement, balance, and coordination.
The researchers thus believe that restoring GLS1 expression could be a promising strategy to revive the muscle-repairing power that declines with age.
The findings are very promising, although most results to date come from mouse models. To move toward real clinical treatment, researchers need to confirm whether the same pathways and effects also occur in human stem cells.
Written for you by our author Sanjukta Mondal, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive.
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Publication details
David E. Lee et al, Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis, Nature Aging (2026). DOI: 10.1038/s43587-026-01120-3
Journal information:
Nature Aging
Key medical concepts
Clinical categories
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