Ageing Muscles May Trade Strength for Protection, Copenhagen Mouse Study Finds

Muscles weaken as people get older, and for a long time the shift in their makeup that comes with age looked like plain decline. New work from the University of Copenhagen suggests part of it may be a defence. The researchers found that ageing muscle gives up some power to protect its own cells from damage.

The puzzle they set out to solve was a strange one. Muscle contains bundles of fibres with different jobs. Fast-twitch fibres produce powerful, rapid movements but tire quickly. Slow-twitch fibres support sustained activity and hold more mitochondria, the structures that make much of a muscle's energy. With age, strength falls and mitochondria grow less efficient. Yet ageing muscle also ends up with a larger share of slow-twitch fibres, which lean hardest on the mitochondria that are faltering. Similar changes appear in several conditions that waste muscle. Why would muscle rely more on a system that is working less well?

The team focused on cardiolipin, a specialised fat found almost entirely in the inner membrane of mitochondria, where it helps hold the membrane's folded shape. Without enough of it, mitochondria struggle to generate energy and to produce the chemical signals and materials cells need. The researchers found that cardiolipin levels drop in muscle mitochondria from both mice and humans as they age or become ill, and that the drop comes with structural abnormalities and loss of normal function.

To test whether the loss was a cause rather than a bystander, they lowered cardiolipin in young mice. The results closely resembled natural ageing, with muscle fibres moving from fast-twitch toward slow-twitch. Then they restored cardiolipin to roughly two-thirds of its normal concentration. That began reversing the muscle wasting and completely prevented the premature deaths seen in the affected animals.

Further experiments pointed to a protective explanation. When cardiolipin falls, damaged mitochondria release far more reactive oxygen species, or ROS. These molecules can injure cell structures, but they also signal that something is wrong, and the researchers found they help start the switch from fast to slow fibres. Treating cardiolipin-deficient muscle cells with an antioxidant made the transformation less pronounced. A protein called ERRγ coordinates the response, directing cells to reorganise their mitochondria and change their fibre characteristics. When scientists inhibited it in lab-grown muscle cells, the fibre transition stopped entirely.

The remodelled fibres also defend themselves in a specific way. Mice short on cardiolipin took up considerably more glucose from their blood, but their muscles were not mainly burning it for energy. Experiments tracking labelled glucose showed the cells diverted the sugar into making their own antioxidants, guarding against the excess ROS. "The fiber switch is not the muscle failing, but the muscle trading power for protection," said Assistant Professor Fabian Finger, first and co-corresponding author. That is also why interfering can backfire: when the mice were given antioxidants to mop up ROS, their muscles fared worse, not better.

The caveats are significant. The experiments showing the protective mechanism and the reversal of wasting were done in mice. Human muscle samples were used only to show that cardiolipin also declines with age in people. Still, there are existing footholds. The FDA recently granted accelerated approval to elamipretide, a drug meant to stabilise cardiolipin, for Barth syndrome, a rare inherited disorder, which suggests targeting the molecule is feasible, though whether it helps ordinary age-related muscle loss is unknown. ERRγ belongs to the nuclear receptor family, which are targets for roughly 10 to 15 per cent of FDA-approved small-molecule drugs, and drugs that activate it are being studied in preclinical research for other uses.

"What encourages me most is that even a partial recovery of cardiolipin was enough to bring the muscle back," said senior author Zachary Gerhart-Hines, Associate Professor at the NNF Centre for Basic Metabolic Research. The open question, he said, is whether cardiolipin can be raised in ageing muscle, or ERRγ targeted, to promote healthy adaptations. Human trials would have to answer it.