Blocking a Glutamine Enzyme Restores Aging Muscle Power in Mice

Skeletal muscle is more than the machinery of movement. It is the body’s largest metabolic organ, accounting for more than 35 percent of body mass, and its slow erosion with age—sarcopenia—robs millions of people of mobility, independence, and quality of life. Now, a team at the University at Buffalo reports that a single metabolic switch, the enzyme glutaminase 1, helps drive that decline, and that shutting it down with an experimental drug can restore mitochondrial function, muscle fiber size, and even grip strength in mice with accelerated aging. The study, published in Aging Cell, adds a striking new entry to the short list of interventions that appear to reverse, rather than merely slow, hallmarks of muscle aging.

The researchers, led by Stelios T. Andreadis, focused on a puzzle that has been building in the aging field for years. Senescent cells—the damaged, growth-arrested cells that accumulate in aging tissues—are known to suffer from failing mitochondria, the cellular power plants that generate ATP through the electron transport chain. At the same time, senescent cells are known to lean heavily on glutamine, an amino acid they consume and break down to survive. The Buffalo group had previously shown that ramped-up glutamine catabolism impairs mitochondrial function in senescent mesenchymal stromal cells. What remained unknown was whether the same metabolic drift occurs in skeletal muscle cells and, crucially, whether it could be targeted in a living animal.

The first clue came from an unexpected molecule: urea. When the team induced senescence in human myoblasts—muscle stem-like progenitor cells—using three independent methods, including DNA damage with etoposide, oxidative stress with hydrogen peroxide, and simple replicative exhaustion, all three senescent states showed a significant rise in intracellular urea compared with young, proliferating cells. To test whether urea was a cause rather than a byproduct of dysfunction, the researchers knocked down SLC14A1, the urea transporter, in healthy young myoblasts, forcing urea to accumulate. The result was dramatic: mitochondrial membrane potential collapsed, protein levels of the electron transport chain complexes fell sharply, and oxygen consumption—measured with a Seahorse extracellular flux analyzer—plummeted across basal, ATP-linked, maximal, and spare respiratory capacity. The urea-laden young cells also accumulated DNA damage, marked by γ-H2AX foci, and senescence-associated beta-galactosidase activity, two classic hallmarks of cellular aging.

That finding pointed straight back to glutamine. The enzyme GLS1 catalyzes the deamination of glutamine, and its expression was elevated at both the mRNA and protein levels in every senescence model the team examined. When the researchers treated senescent myoblasts with CB-839, a selective GLS1 inhibitor also known as telaglenastat, glutaminase activity and intracellular urea both fell in a dose-dependent fashion, with a significant reduction in urea at just 0.5 micromolar. Higher doses began to kill the cells outright, so the team settled on the low, non-lethal dose for all subsequent experiments. Within five days of treatment, the senescent myoblasts had rebuilt key electron transport chain components, including COX-I, COX-II, and COX-IV; their mitochondrial membrane potential rebounded; and their respiration improved across every parameter measured. DNA damage markers dropped as well. Notably, the drug left the mitochondria of young, proliferating myoblasts untouched, suggesting its effects are specific to the senescent state rather than a general metabolic stimulant.

The team then traced the upstream wiring. Among the three major MAPK signaling pathways—ERK, JNK, and p38—it was p38 that emerged as the dominant regulator of GLS1 in senescent myoblasts. Pharmacological inhibition of p38 with SB203580, and with two additional inhibitors, SB202190 and ralimetinib dimesylate, lowered GLS1 mRNA and protein, boosted electron transport chain protein abundance, and restored respiratory function at the highest dose tested. The finding carries an intriguing wrinkle: in the group’s earlier work on senescent stromal cells, JNK, not p38, had been the key GLS1 regulator. The conservation of the glutaminase-to-urea-to-mitochondrial-dysfunction axis across cell types, paired with cell-type-specific upstream switches, suggests a shared logic of metabolic aging that may be targetable at multiple points.

The decisive test came in vivo. The researchers used heterozygous LAKI mice, which carry the Lmna G609G mutation underlying Hutchinson-Gilford progeria syndrome, a devastating human disease of premature aging caused by accumulation of the mutant protein progerin. These mice develop progressive musculoskeletal and cardiovascular abnormalities and are widely used to evaluate anti-aging therapies. Ten-month-old progeria mice received intraperitoneal injections of CB-839 at 10 milligrams per kilogram three times a week for one month. Compared with wild-type controls, the gastrocnemius muscle of untreated progeria mice showed elevated glutaminase activity and urea concentration; both fell significantly after treatment. Treated muscle also displayed lower reactive oxygen species and higher levels of the COX-I, COX-II, and COX-IV electron transport chain complexes.

The structural and functional consequences were substantial. The cross-sectional area of myofibers in the tibialis anterior increased significantly in treated animals, and the number of Pax7-positive satellite cells—the resident stem cells that fuel muscle regeneration—rose as well. Most strikingly, direct in situ measurements of the dorsiflexor muscles showed that untreated progeria mice lost muscle strength over time, while treated mice did not: twitch force and maximum isometric tetanic force both climbed above baseline, and relaxation times shortened toward normal. The improvements translated into whole-animal performance. Treated mice walked faster on a gait track and hung longer on an inverted wire grid, a measure of grip endurance, than their untreated counterparts.

To probe whether the drug had reprogrammed the muscle’s regenerative cells themselves, the team isolated myoblasts from the gastrocnemius of treated and untreated progeria mice. The treated animals’ myoblasts retained reduced GLS1 activity and lower urea content even after removal from the body, along with higher mitochondrial membrane potential, better respiratory chain activity, less DNA damage, and reduced expression of inflammatory cytokines including IL1α, IL1β, and CCL8. When coaxed to differentiate, these cells formed myotubes with a higher fusion index and greater width than myoblasts from untreated progeria mice, whose defective fusion is a known barrier to muscle repair. Because mitochondrial DNA content was unchanged, the authors conclude that the drug improved the functional capacity of the existing mitochondrial pool rather than increasing mitochondrial quantity.

One subtlety distinguishes this work from the growing senolytics literature. Previous studies showed that high-dose glutaminase inhibition can kill senescent cells by acidifying their interior. Here, the low dose of CB-839 did not eliminate senescent cells—senescence-associated beta-galactosidase activity persisted—yet mitochondrial function and muscle performance improved anyway. The benefit appears to come from metabolic restoration within senescent cells rather than their removal, a mechanism the authors describe as independent of senolytic activity. That distinction matters therapeutically, because it suggests a gentler intervention that rejuvenates rather than depletes the senescent pool, at least in muscle.

The translational hook is hard to ignore. CB-839 has already been through clinical development as an anticancer agent, on the logic that tumors exploit glutaminolysis to fuel rapid proliferation. Repurposing it, or related glutaminase inhibitors now in the oncology pipeline, for sarcopenia would shortcut years of early safety work. The authors caution that open questions remain: the study did not examine sex-specific responses despite including both male and female mice, and the long-term effects of GLS1 inhibition on lifespan and healthspan are unknown. Still, the paper sketches a coherent chain of causation—p38 signaling drives GLS1, GLS1 drives urea accumulation, urea cripples mitochondria, and crippled mitochondria wither muscle—and demonstrates that breaking the first link can restore strength in a progeroid animal. If the same axis operates in ordinary human aging, the body’s most abundant organ may one day be treated not with exercise alone, but with a drug that teaches aging cells to stop poisoning their own power plants.

Subject of Research: Glutaminase inhibition as a therapy for senescence-associated mitochondrial dysfunction and skeletal muscle aging

Article Title: Inhibiting Glutaminase Reverses Senescence‐Associated Mitochondrial Dysfunction and Skeletal Muscle Decline

Article References: Senthil Kumar, H. V., Choudhury, D., Lei, P., Mehrotra, P., Shahini, S., Swedick, S., Toftegaard, J., & Andreadis, S. T. (2026). Inhibiting Glutaminase Reverses Senescence‐Associated Mitochondrial Dysfunction and Skeletal Muscle Decline. Aging Cell, 25(10), Article e70703. https://doi.org/10.1111/acel.70703

Image Credits: AI Generated

DOI: 10.1111/acel.70703

Keywords: glutaminase, GLS1, CB-839, telaglenastat, sarcopenia, mitochondria, cellular senescence, urea, progeria, skeletal muscle, p38 MAPK, aging