Scientists discover a hidden reason why muscles weaken with age
Scientists have uncovered a hidden defense mechanism in aging muscles that sacrifices strength to protect cells from damage. In mice, partially restoring a crucial molecule reversed signs of muscle wasting and prevented premature death, raising hopes for new treatments for age-related muscle decline.
Key points
- Researchers found that aging muscles shift toward slow-twitch fibers as a protective response to declining cardiolipin and rising reactive oxygen species.
- Lowering cardiolipin in young mice reproduced the aging pattern, while restoring it to about two-thirds of normal levels began reversing muscle wasting.
- The experiments were in mice; human samples were used only to confirm that cardiolipin levels decline with age.
Scientists have found that some changes in aging muscle may be protective rather than purely harmful. As people age, muscles lose strength and their mitochondria become less efficient, yet they also develop a greater share of slow-twitch fibers, which rely heavily on those mitochondria. Researchers set out to explain why muscles would lean on a system that is failing.
The work focused on cardiolipin, a fat molecule found almost exclusively in the inner membrane of mitochondria, where it helps maintain the membrane's folded structure. The team found cardiolipin levels drop in muscle mitochondria from both mice and humans as they age or develop disease, alongside structural abnormalities and lost function. The research was led by the NNF Center for Basic Metabolic Research at the University of Copenhagen with the University of Southern Denmark and more than 20 institutions.
A protective trade-off
When cardiolipin falls, damaged mitochondria release far more reactive oxygen species (ROS), which can harm cells but also signal problems. The researchers found ROS help trigger the switch from fast-twitch to slow-twitch fibers, and an antioxidant treatment made the transformation less pronounced. A protein called ERRγ coordinates the response; blocking it in lab-grown muscle cells stopped the fiber transition entirely.
Mice lacking cardiolipin took in much more glucose from the blood, but tracked labeled glucose showed the sugar went toward making the muscles' own antioxidants rather than energy. Assistant Professor Fabian Finger of the University of Copenhagen said the fiber switch is the muscle "trading power for protection" and that giving the mice antioxidants made their muscles fare worse.
The fiber switch is not the muscle failing, but the muscle trading power for protection.
— Assistant Professor Fabian Finger
Possible treatment paths
The experiments showing the protective mechanism and reversal of muscle wasting were done in mice; human samples only established that cardiolipin declines with age. The FDA recently granted accelerated approval to elamipretide, which helps stabilize cardiolipin, for Barth syndrome, suggesting the molecule can be targeted medically, though its effect on ordinary age-related muscle loss is unknown. ERRγ is also a potential target, and drugs that activate it are in preclinical research.
Senior author Zachary Gerhart-Hines, an Associate Professor at the University of Copenhagen, said even a partial cardiolipin recovery was enough to bring muscle back. Funding came from the Novo Nordisk Foundation, European Research Council, Lundbeck Foundation and US National Institutes of Health, among others.
