Muscles naturally weaken with age, but the findings suggest that some changes associated with this process may serve a protective purpose. The research explains why ageing muscles increasingly shift towards a different type of muscle fibre and identifies a molecule that could become a target for future treatments.
Muscle tissue contains bundles of fibres with distinct functions. Fast-twitch fibres generate powerful, rapid movements but tire relatively quickly. Slow-twitch fibres, in contrast, support sustained activity and contain higher concentrations of mitochondria, the cellular structures responsible for producing much of the energy muscles require. The study was reported by ScienceDaily.
As people grow older, muscle strength declines and mitochondria become less efficient. Yet ageing muscles also develop a higher proportion of slow-twitch fibres, despite these fibres relying heavily on mitochondria whose ability to function is deteriorating. Researchers have observed similar changes in several conditions associated with muscle wasting.
The apparent contradiction prompted scientists to investigate why muscles increasingly depend on an energy-producing system that is becoming less effective.
The team focused on cardiolipin, a specialised fat molecule found almost exclusively in the inner membrane of mitochondria. Cardiolipin helps maintain the membrane's distinctive folded structure, which is essential for normal mitochondrial activity.
When cardiolipin is deficient, mitochondria struggle to produce sufficient energy. They also become less capable of generating the chemical signals and essential materials required by cells to function properly.
Researchers found that cardiolipin levels decline in muscle mitochondria in both mice and humans as they age or develop disease. This reduction was accompanied by structural abnormalities in mitochondria and a loss of normal function, according to ScienceDaily.
To determine whether the decline in cardiolipin directly contributed to these changes rather than merely occurring alongside them, scientists experimentally reduced its levels in young mice.
The resulting changes closely resembled those associated with natural ageing. The animals' muscle fibres shifted away from the fast-twitch type towards slow-twitch fibres, reproducing a pattern previously observed in older mice and humans.
The researchers then restored cardiolipin to approximately two-thirds of its normal concentration. This partial recovery began reversing muscle wasting and completely prevented the premature deaths observed in the affected animals.
Further experiments revealed why the shift towards slow-twitch fibres may occur. Rather than being solely a sign of deteriorating muscle function, the transformation appears to be part of a protective response to mitochondrial stress.
When cardiolipin levels fall, damaged mitochondria produce substantially larger quantities of reactive oxygen species (ROS). These highly reactive molecules can damage cellular structures, but they also act as signals that alert cells to problems.
The researchers found that ROS help trigger the transition from fast-twitch to slow-twitch muscle fibres. When they treated muscle cells lacking cardiolipin with an antioxidant to reduce ROS, the transition became less pronounced.
A protein called ERRγ plays a central role in coordinating this response. It directs cells to reorganise their mitochondria and alter their muscle fibre characteristics. When researchers inhibited ERRγ in muscle cells grown in the laboratory, the transition between fibre types stopped entirely, according to the study reported by ScienceDaily.
The team also identified how the remodelled muscle fibres protect themselves against cellular damage.
Mice with insufficient cardiolipin absorbed considerably more glucose from their bloodstream. However, their muscles did not primarily use this additional sugar to generate energy.
Instead, experiments using specially labelled glucose revealed that muscle cells redirected the sugar towards producing their own antioxidants. This process helped protect the cells against damage caused by excess 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,” said Assistant Professor Fabian Finger, the first and co-corresponding author from the University of Copenhagen.
The findings point to possible new approaches for treating age-related muscle decline, although the evidence remains at an early stage. The experiments demonstrating the protective mechanism and reversal of muscle wasting were conducted in mice. Human muscle samples were used only to establish that cardiolipin levels also decline with age in people.
Researchers already have potential ways to influence cardiolipin levels. The FDA recently granted accelerated approval to elamipretide, a medication designed to help stabilise cardiolipin, for Barth syndrome, a rare inherited disorder. This indicates that targeting the molecule is medically feasible, although whether the medication can help treat ordinary age-related muscle loss remains unknown.
ERRγ is another potential therapeutic target because of its role in helping muscles adapt to mitochondrial stress.
The protein belongs to a family of molecules known as nuclear receptors. These proteins are established targets for approximately 10 to 15 per cent of FDA-approved medications made from small molecules. Drugs that activate ERRγ are also being investigated in preclinical research for other medical applications, according to ScienceDaily.
The findings suggest that future therapies could focus on restoring cardiolipin levels or influencing the protective adaptations regulated by ERRγ. Such approaches would aim to address the biological changes associated with ageing muscles while accounting for the protective role of the body's response to mitochondrial stress.
“What encourages me most is that even a partial recovery of cardiolipin was enough to bring the muscle back. The question now is whether we can increase cardiolipin in aging muscle or target ERRγ to promote healthy adaptations. This is where the therapeutic potential lies,” said senior author Zachary Gerhart-Hines, Associate Professor at the NNF Centre for Basic Metabolic Research, University of Copenhagen.
The research highlights a potential distinction between muscle changes that directly contribute to weakness and those that help limit further damage. Whether restoring cardiolipin or targeting ERRγ can safely preserve muscle strength in ageing humans remains to be established through further research.
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