Blocking one enzyme revived the power plants of aging muscle cells, and made fast-aging mice stronger

With age, muscles lose size and strength, a condition called sarcopenia. One suspected reason is that the mitochondria inside muscle cells, the tiny power plants that burn fuel with oxygen to make the cell's energy, work less well. A team at the University at Buffalo now points to a link between those power plants and the way aging muscle cells handle glutamine, one of the amino acids that proteins are built from.

When cells use glutamine for fuel or building material, the first step is done by an enzyme called glutaminase (the main form is GLS1), which strips a nitrogen group off glutamine. Nitrogen that the cell doesn't need ends up in urea, the waste product best known from urine. The same team had earlier found that stem-like cells from connective tissue that had stopped dividing broke down more glutamine, and that this hurt their mitochondria.

What they did

The researchers worked with myoblasts, the young muscle cells that fuse together to build and repair muscle fibers. The cells came from three donors aged 68, 18 and 17. They pushed the cells into senescence, a state in which cells stop dividing for good but don't die, in three ways: a drug that damages DNA, repeated doses of hydrogen peroxide (a chemical stress), and simply letting the cells divide until they gave up.

They then treated the aged cells for five days with CB-839, a drug that blocks glutaminase. In young cells, they switched off a channel that carries urea out of the cell, to see what trapped urea does on its own.

Finally, they gave CB-839 to mice carrying one copy of a mutation in the lamin A gene that, in people, causes progeria, a disease of very early aging. At 10 months these mice already show signs of aging. Male and female mice got an injection of CB-839 (10 mg per kg of body weight) or a dummy injection three times a week for a month, and were compared with normal mice of the same age.

What they found

• More urea, weaker mitochondria. In all three kinds of aged cells, urea built up inside the cells and glutaminase was more abundant. Trapping urea in young cells was enough to weaken their mitochondria: they had fewer of the proteins of the electron transport chain (the assembly line that uses oxygen to make energy), used less oxygen, and showed more DNA damage.
• Blocking glutaminase helped the cells. A low dose of CB-839 (0.5 micromolar) lowered urea, brought back the energy-making proteins, raised oxygen use and reduced DNA damage. This was seen in cells from more than one donor.
• It did not remove the aged cells. A standard stain for senescent cells did not change, so the drug seems to repair them rather than kill them. In young, healthy cells it had no effect on the mitochondria measure tested.
• A signal upstream. Blocking a stress-signalling protein called p38 lowered glutaminase levels and also improved the mitochondria of the aged cells.
• In the mice. Treated mice had less glutaminase activity and less urea in their calf muscle, more energy-making proteins, larger muscle fibers and more satellite cells, the muscle's own stem cells. The untreated fast-aging mice lost strength over the month; the treated ones did not, and their muscles relaxed faster after contracting. They also walked faster and hung on longer to an upside-down wire grid.
• Lasting changes. Muscle cells taken out of treated mice (pooled from five per group) and grown in a dish still had less urea, better-working mitochondria, less DNA damage and lower activity of some inflammation genes, and they fused into muscle fibers more readily.

What to keep in mind

• Cells and mice only. No person took part. The human data come from cells of just three donors, aged in the dish with stress or many divisions.
• A model of early aging. The mice carry a progeria mutation; they are not naturally old mice. The groups were small: most tests used 5 mice per group (3 male, 2 female), others 4 to 8.
• Short treatment. The mice were treated for one month. The authors note that long-term effects on lifespan and health still have to be studied, and that they did not check whether the drug works differently in males and females.
• Open questions about how. The authors say the mechanisms by which blocking glutaminase improves the mitochondria "warrant further investigation". The cells' mitochondria worked better, but there weren't more of them.
• An experimental cancer drug. CB-839 (telaglenastat) has been tested in people as a cancer treatment, because many tumors depend on glutamine. In this study higher doses harmed muscle cells in the dish. It is not a drug for muscle aging.

Why it matters

The study proposes a chain of events in aging muscle: a stress signal raises glutaminase, the cells break down more glutamine, urea builds up, and the mitochondria falter. The authors raise the "possibility" that glutaminase blockers developed for cancer could be repurposed against sarcopenia, and say this needs further investigation. Whether anything like this would help older people's muscles, and at what risk, is a question for future studies.