Scientists uncover a hidden reason why muscles weaken with age
University of Copenhagen researchers found that the shift in muscle fibre types during aging is a protective response linked to the mitochondrial molecule cardiolipin. The findings, obtained mainly in mice, could point toward new treatments for age-related muscle loss.
Scientists at the University of Copenhagen in Denmark have worked out why aging muscles rely more and more on slow-twitch fibres, even though these depend on mitochondria, the cell structures that produce much of a muscle's energy, which become less efficient with age. The study suggests the change is a protective mechanism and points to a possible new approach for treating muscle loss.
Two types of fibre
Muscle contains fast-twitch fibres, which produce powerful, rapid movements but tire quickly, and slow-twitch fibres, which support sustained activity and hold more mitochondria. With age, strength declines while the share of slow-twitch fibres grows. Similar shifts have been seen in several conditions that cause muscle wasting.
The role of cardiolipin
The researchers focused on cardiolipin, a fat molecule found almost exclusively in the inner membrane of mitochondria, where it helps maintain the membrane's folded structure. Its levels fall in the muscles of both mice and humans with age or disease, and the mitochondria become structurally abnormal. When the team lowered cardiolipin in young mice, their muscle fibres shifted in a way that mirrored natural aging. Restoring about two-thirds of the normal level began reversing muscle wasting and fully prevented the premature deaths seen in the affected animals.
Protection rather than simple damage
With too little cardiolipin, damaged mitochondria produce far more reactive oxygen species (ROS). These molecules can harm cells but also act as a warning signal that helps trigger the switch from fast to slow fibres. A protein called ERRγ coordinates the response; when it was inhibited in laboratory-grown muscle cells, the transition stopped completely. Mice lacking cardiolipin took up more glucose, but their muscles used it to make their own antioxidants rather than energy.
"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," said Assistant Professor Fabian Finger of the University of Copenhagen.
Limits and prospects
The experiments showing the protective mechanism and the reversal of muscle wasting were done in mice; human samples were used only to confirm that cardiolipin falls with age. The US Food and Drug Administration (FDA) recently granted accelerated approval to elamipretide, a drug designed to stabilize cardiolipin, for Barth syndrome, a rare inherited disorder, but its effect on ordinary age-related muscle loss is unknown. The work was led by the NNF Center for Basic Metabolic Research at the University of Copenhagen and involved scientists from more than 20 institutions.
