Restoring just part of a depleted mitochondrial fat began reversing muscle wasting in mice, suggesting a possible route toward treating age-related muscle decline.
As muscles weaken with age, they shift toward fibers built for endurance rather than quick, powerful bursts of movement. These slow-twitch fibers contain more mitochondria, the structures that supply cells with energy, than fast-twitch fibers, which tire more quickly. Yet mitochondria also become less effective with age, leaving older muscles increasingly dependent on machinery that is struggling to do its job.
Experiments in mice and cultured muscle cells suggest that this shift, also seen in many muscle-wasting diseases, helps cells withstand damage from their strained mitochondria. Researchers at the University of Copenhagen traced the response to a shortage of cardiolipin, a fat molecule found almost exclusively in the inner membrane of mitochondria. Cardiolipin maintains the membrane’s distinctive folded structure, which mitochondria need to supply enough energy, metabolic signals, and building blocks for cells.
The researchers found that cardiolipin levels declined in muscle mitochondria with aging and disease, leaving the structures distorted and functioning poorly. Human muscle samples confirmed that cardiolipin also falls with age in people, while experiments in mice and cultured muscle cells explored the consequences. To establish whether the loss could cause muscle changes rather than simply accompany them, the team reduced cardiolipin in young mice to mimic the decline associated with aging. Their muscles developed the same shift from fast-twitch to slow-twitch fibers seen in older mice and humans.
Sugar redirected toward muscle defenses
The altered muscles also handled sugar differently. Mice deficient in cardiolipin drew much more glucose from the bloodstream, but tracing labeled sugar through their muscles revealed that it was being used to manufacture the cells’ own antioxidants rather than being burned for energy. Those antioxidants helped the remodeled slow-twitch fibers protect cells against reactive oxygen species, or ROS, molecules that can damage cells.
“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 Fabian Finger, an assistant professor at the University of Copenhagen and the study’s first and co-corresponding author.
ROS also act as a signal that helps set this protective response in motion. As cardiolipin levels fall, stressed mitochondria produce far more ROS. Removing them with an antioxidant in cardiolipin-depleted muscle cells blunted the shift toward slow-twitch fibers. The response operates through a protein called ERRγ, which prompts cells to remodel their mitochondria and change fiber type. Blocking ERRγ in cultured muscle cells stopped the switch completely.
Restoring cardiolipin reduces wasting in mice
Restoring the missing fat addressed the mitochondrial problem more directly. When the researchers brought cardiolipin back to roughly two-thirds of its normal level in the mice, muscle wasting began to reverse, and the animals’ early deaths were prevented entirely.
“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, an associate professor at the NNF Center for Basic Metabolic Research at the University of Copenhagen.
A drug proposed to stabilize cardiolipin, elamipretide, recently received accelerated FDA approval for Barth syndrome, a rare genetic disorder. That approval provides an existing example of a treatment directed at cardiolipin, although the muscle recovery reported in this study was demonstrated in mice.
ERRγ offers another possible route for drug development. 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. Compounds that activate ERRγ are already in preclinical development for other conditions.
Reference: “Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ” by Fabian Finger, Mikkel Frost, Shinya Watanabe, Tao Ma, Taewook Kang, Dipsikha Biswas, Ruben Zapata-Perez, Vincent Anton, Lucile Dollet, Lasse K. Markussen, Nanami Senoo, Iuliia Karavaeva, Astrid Linde Basse, Oksana Dmytriyeva, Tara TeSlaa, Jesper F. Havelund, Amy M. Ehrlich, Marta Moreno-Torres, Caio Yogi Yonamine, Nicoline R. Andersen, Ida Blom, Francisco Garcia-Carrizo, Piyarat Siripoksup, Magnus Asping, Thomas S. Nielsen, Marcus Nygård, Anders B. Klein, Andrey Tvardovskiy, Trine S. Nicolaisen, Carlos Durantez-Fernández, Klaus Qvortrup, Clara Prats, Joshua D. Rabinowitz, Christoffer Clemmensen, Lykke Sylow, Juleen R. Zierath, Jonas T. Treebak, Tim J. Schulz, Trisha J. Grevengoed, Steven M. Claypool, Julien Prudent, Rob C. I. Wüst, Susanne Mandrup, Riekelt H. Houtkooper, Kei Sakamoto, Nils J. Færgeman, Martin R. Larsen, Katsuhiko Funai, Steen Larsen and Zachary Gerhart-Hines, 29 September 2026, Nature Aging.
DOI: 10.1038/s43587-026-01227-7
The work was funded by the European Research Council, the Lundbeck Foundation, and the US National Institutes of Health, among others.
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