When they then partially restored cardiolipin to about two-thirds of normal levels, the muscle wasting began to reverse, and the animals' early deaths were prevented entirely. Human tissue samples confirmed only that cardiolipin also declines with age in people — the intervention itself was tested in mice alone.

Why do muscles make this switch at all?

The answer surprised the researchers: it is a defense mechanism, not a failure.

As cardiolipin falls, strained mitochondria produce far more reactive oxygen species (ROS) — chemically reactive molecules that damage cells. But ROS also act as an alarm signal. When the scientists used an antioxidant to mop up ROS in cardiolipin-depleted muscle cells, the shift toward slow-twitch fibers was blunted.

The switch itself runs through ERRγ, a nuclear receptor — a class of proteins that turns genes on and off and that roughly 10% to 15% of all FDA-approved small-molecule drugs already target. When the scientists blocked ERRγ in cultured muscle cells, the fiber switch shut down completely.

The remodeled slow-twitch fibers protect the cell through an unusual use of sugar. Cardiolipin-deficient mice pulled much more glucose from the bloodstream, but not to burn for energy. By tracing labeled sugar through muscle tissue, the researchers showed the glucose was instead used to manufacture the cells' own antioxidants.

"The fiber switch is not the muscle failing, but the muscle trading power for protection," said Fabian Finger, assistant professor at the University of Copenhagen and the study's first and co-corresponding author. "That's also why interfering with it can backfire: When we gave the mice antioxidants to mop up the ROS, their muscles fared worse, not better."

What are the drug possibilities?

Two therapeutic paths emerge from the findings, though both remain preliminary.

• Cardiolipin itself can already be targeted. The FDA recently granted accelerated approval to elamipretide, a drug proposed to stabilize cardiolipin, for the rare genetic disorder Barth syndrome.
• ERRγ is a promising target. Activators of ERRγ are already in preclinical development for other indications.

Senior author Zachary Gerhart-Hines, associate professor at the NNF Center for Basic Metabolic Research at the University of Copenhagen, said: "What encourages me most is that even a partial recovery of cardiolipin was enough to bring the muscle back. The question now is whether we can increase cardiolipin in aging muscle or target ERRγ to promote healthy adaptations. This is where the therapeutic potential lies."

What are the study's limits?

The caveats matter. The intervention experiments were carried out in mice; the human samples served only to confirm that cardiolipin declines with age in people. Whether raising cardiolipin or modulating ERRγ can preserve muscle function in aging humans remains an open question — and the mouse data on antioxidants suggest that bluntly interfering with the fiber switch could do more harm than good.

Publication details: Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ, Nature Aging (2026). DOI: 10.1038/s43587-026-01227-7