Our muscles are built from bundles of fibers. Some are fast twitch, tuned for quick, powerful bursts of effort but quick to tire. Others are slow twitch, built for endurance and packed with more mitochondria, the structures commonly called the ‘powerhouses of the cell.’
As we age, our muscles grow weaker, and the mitochondria inside them work less well. Yet at the same time, our muscles shift toward slow-twitch fibers that depend most on mitochondria. A similar shift occurs in many diseases that cause muscle wasting. It’s paradoxical: why would aging muscle lean harder on the very machinery that is failing?
To understand the enigma, the researchers turned to cardiolipin, a fat molecule found essentially nowhere else in the cell but the inner membrane of mitochondria, where it is essential for the membrane’s unique folded structure. Without it, mitochondria are unable to produce enough energy or the metabolic signals and building blocks that cells need.
The scientists found cardiolipin levels decline in mouse and human muscle mitochondria with age and disease, leaving the mitochondria distorted and unable to operate properly.
To test whether falling cardiolipin was a cause rather than a consequence, the scientists lowered cardiolipin levels in young mice to mimic the drop seen in aging. They saw the same fast-to-slow-twitch shift in muscle fibers that occurs naturally in aged mice and humans. When cardiolipin levels were partially recovered to roughly two-thirds of normal, the muscle wasting began to reverse, and the animals’ early deaths were prevented entirely.
So why do muscles respond this way? The answer was surprising: it’s a defense mechanism.
As cardiolipin levels decline, strained mitochondria generate far more reactive oxygen species (ROS), which damage cells. But ROS is also a signal: when the researchers 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 a protein called ERRγ, which triggers the cells to remodel their mitochondria and change fiber type from fast to slow twitch. When the scientists blocked ERRγ in cultured muscle cells, the fiber switch was completely shut down.
The remodeled slow-twitch fibers better protect the cell from ROS because of what they do with sugar. Cardiolipin-deficient mice pulled much more glucose out of the bloodstream, but not to burn for energy. By tracing labeled sugar through the muscle, the researchers showed it was instead used to manufacture the cell's own antioxidants.
“The fiber switch is not the muscle failing, but the muscle trading power for protection. 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,” says Assistant Professor Fabian Finger, first and co-corresponding author, from the University of Copenhagen.
The work was carried out in mice, and the human samples served only to confirm that cardiolipin also declines with age in people. However, cardiolipin 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 also a promising target. It belongs to a class of molecules called nuclear receptors, which are targeted by roughly 10 to 15 percent of all FDA-approved small-molecule medications, and activators of ERRγ are already in preclinical development for other indications.
“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,” says senior author Zachary Gerhart-Hines, Associate Professor at the NNF Center for Basic Metabolic Research, University of Copenhagen.
---
The study spanned more than 20 institutions, led by the NNF Center for Basic Metabolic Research at the University of Copenhagen with the Center for Adipocyte Signaling at the University of Southern Denmark. In addition to the Novo Nordisk Foundation, the work was funded by the European Research Council, the Lundbeck Foundation and the US National Institutes of Health, among others.
Read the paper in Nature Aging : ‘Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via ERRγ’. Link https://www.nature.com/articles/s43587-026-01227-7
DOI: 10.1038/s43587-026-01227-7
Contact
Zach Gerhart-Hines | Associate Professor | NNF Center for Basic Metabolic Research, University of Copenhagen | zpg@sund.ku.dk | +45 60 67 06 82
Fabian Finger | Assistant Professor | Department of Biomedical Sciences, University of Copenhagen | fabian.finger@sund.ku.dk| +45 91 43 74 03
Nature Aging
Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ
29-Sep-2026
Z.G.-H. works, in some capacity, for Embark Laboratories ApS, a company developing therapeutics for the treatment of diabetes and obesity. The other authors declare no competing interests.