Muscles weaken as we get older, and the mitochondria inside them, the structures that produce much of their energy, become less efficient. That part is expected. What has puzzled researchers is that ageing muscle also shifts toward slow-twitch fibres, the type that depends most heavily on mitochondria. Why would a muscle lean harder on an energy system that is failing? A study from the University of Copenhagen, published in Nature Aging, proposes an answer: the shift is a trade, giving up power in exchange for protection.

Fast fibres, slow fibres and a paradox

Muscle is built from bundles of fibres with different jobs. Fast-twitch fibres deliver powerful, rapid movements but tire quickly. Slow-twitch fibres support sustained activity and contain more mitochondria. With age, the proportion of slow-twitch fibres rises, which looks paradoxical given that their mitochondria are the part that is deteriorating. Similar shifts have been seen in several conditions that cause muscle wasting.

A fat molecule in the spotlight

The team focused on cardiolipin, a specialised lipid found almost exclusively in the inner membrane of mitochondria, where it helps maintain the membrane’s folded structure. Without enough of it, mitochondria struggle to produce energy and the other materials and signals cells need.

The researchers report that cardiolipin levels in muscle mitochondria fall with age and disease in both mice and humans, alongside structural abnormalities and loss of function. To test whether the drop is a cause rather than a bystander, they lowered cardiolipin in young mice. The muscles of these animals moved away from fast-twitch toward slow-twitch fibres, resembling the pattern seen in older mice and people.

Restoring cardiolipin to roughly two-thirds of its normal level began to reverse the muscle wasting in these mice and fully prevented the early deaths seen in the affected animals.

Power traded for protection

Why would the muscle switch fibre type? The proposed explanation runs through reactive oxygen species (ROS), reactive molecules that can damage cell structures but also act as warning signals. When cardiolipin is low, damaged mitochondria produce much more ROS. In muscle cells lacking cardiolipin, an antioxidant reduced the fibre-type transition, suggesting that ROS help trigger it. A protein called ERRγ appears to coordinate the response, telling cells to reorganise their mitochondria and change fibre type. When ERRγ was blocked in cultured muscle cells, the transition stopped entirely.

The remodelled fibres then defend themselves in a specific way. Mice with too little cardiolipin took up considerably more glucose from the blood, but their muscles did not mainly burn it for energy. Tracing labelled glucose showed that it was being diverted toward making the cells’ own antioxidants.

First author Fabian Finger put it this way: the muscle is trading power for protection. That also explains a counterintuitive result. When the mice were given antioxidants to mop up ROS, their muscles did worse, not better, presumably because the signal that triggers the protective adaptation was being removed.

Possible routes to treatment, and the limits

The authors see two potential targets: raising cardiolipin in ageing muscle, or influencing ERRγ to promote healthy adaptation. Cardiolipin can already be targeted in one setting: the FDA recently granted accelerated approval to elamipretide, a drug designed to stabilise cardiolipin, for Barth syndrome, a rare inherited disorder. Whether it would help ordinary age-related muscle loss is unknown. ERRγ belongs to the nuclear receptor family, which is the target of roughly 10 to 15 percent of FDA-approved small-molecule drugs, and drugs that activate ERRγ are being explored in preclinical research for other uses.

  • The protective mechanism and the reversal of muscle wasting were shown in mice and lab-grown cells. Human muscle samples were used only to show that cardiolipin declines with age in people.
  • The results do not show that antioxidant supplements harm muscle in people. The backfiring effect was observed in mice in this specific experimental setting.
  • No treatment for age-related muscle loss based on this work exists yet. Whether raising cardiolipin or targeting ERRγ would work and be safe in older people has not been tested.

The research involved scientists from more than 20 institutions, led by the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen together with the Center for Adipocyte Signaling at the University of Southern Denmark. Funding came from the Novo Nordisk Foundation, the European Research Council, the Lundbeck Foundation, the US National Institutes of Health and other organisations. This post summarises a research finding and is not medical advice.

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