Scientists at the University of Copenhagen discovered that cardiolipin, a fat molecule in mitochondria, declines with age in both mice and humans. This decline triggers a shift toward slow-twitch muscle fibers, which paradoxically protects aging muscles even as they weaken.
The research team, led by Assistant Professor Fabian Finger and Associate Professor Zachary Gerhart-Hines, experimentally lowered cardiolipin in young mice. The muscles responded by shifting toward slow-twitch fibers, mimicking natural aging. When the researchers restored cardiolipin to roughly two-thirds of normal levels, muscle wasting reversed and premature deaths were prevented.
The mechanism involves damaged mitochondria producing excess reactive oxygen species (ROS). These harmful molecules trigger a protective response through a protein called ERRγ. Muscle cells redirect glucose toward manufacturing antioxidants rather than energy production, defending against the damaging ROS.
"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," Finger said.
The experiments demonstrating reversal occurred in mice. Human muscle samples only confirmed that cardiolipin decreases with age in people.
The FDA recently approved elamipretide, a drug that stabilizes cardiolipin, for Barth syndrome, a rare inherited disorder. ERRγ belongs to a family of proteins already targeted by 10 to 15 percent of FDA-approved medications. The findings suggest future therapies might restore cardiolipin levels or influence ERRγ to promote healthy adaptations.
The work involved scientists from more than 20 institutions and received funding from the Novo Nordisk Foundation, European Research Council, Lundbeck Foundation, and US National Institutes of Health.