Muscles naturally weaken as we age, but scientists have found that some of the changes associated with aging can actually help protect muscle cells from damage. New research reveals why aging muscles switch to a different type of muscle fiber and identifies a crucial molecule that could offer a new approach to treating muscle loss.
Muscle tissue contains bundles of fibers with different functions. Fast-twitch fibers produce powerful, rapid movements but tire relatively quickly. Slow-twitch fibers, on the other hand, support sustained activity and contain higher concentrations of mitochondria, the cellular structures responsible for producing much of the energy muscles need.
As people age, muscle strength declines and mitochondria become less efficient. Surprisingly, aging muscles also develop a greater proportion of slow-twitch fibers, even though these fibers rely heavily on mitochondria that lose their ability to function. Researchers have observed similar changes in several conditions that cause muscle wasting.
This raises an important question: why would muscles rely more and more on a less and less efficient energy production system?
A crucial molecule linked to muscle aging
To study this conundrum, scientists focused on cardiolipin, a specialized fat molecule located almost exclusively in the inner membrane of mitochondria. Cardiolipin helps maintain the distinctive folded architecture of the membrane, essential for proper mitochondrial activity.
When cardiolipin is lacking, mitochondria have difficulty generating enough energy. They also become less able to produce the chemical signals and essential materials that cells need to function.
Researchers have found that cardiolipin levels decrease in the muscle mitochondria of mice and humans as they age or suffer from disease. This decline was accompanied by structural abnormalities in the mitochondria and a loss of normal function.
To determine whether a reduction in cardiolipin directly contributes to these changes, rather than simply occurring alongside them, the team experimentally reduced cardiolipin levels in young mice.
The results looked very similar to what happens during natural aging. Muscle fibers shifted from fast-twitch to slow-twitch fibers, matching the pattern previously observed in mice and older humans.
Even more striking, restoring cardiolipin to about two-thirds of its normal concentration began to reverse muscle wasting and completely prevent the premature deaths seen in affected animals.
Why aging muscles sacrifice strength to protect themselves
Further experiments revealed an unexpected explanation for the transformation. Rather than representing only a decline in muscle function, the shift to slow-twitch fibers appears to be a protective response.
When cardiolipin concentrations fall, damaged mitochondria produce much greater amounts of reactive oxygen species (ROS). These highly reactive molecules can damage cellular structures, but they also play an important role in signaling that something is wrong.
Researchers have found that ROS helps initiate the transition from fast-twitch muscle fibers to slow-twitch muscle fibers. When they treated muscle cells lacking cardiolipin with an antioxidant to reduce ROS, the transformation became less pronounced.
A protein called ERRγ plays a central role in coordinating this response. It asks cells to reorganize their mitochondria and modify the characteristics of their muscle fibers. When scientists inhibited ERRγ in muscle cells grown in the lab, the transition between fiber types stopped completely.
The team also discovered how the newly remodeled fibers help defend themselves.
Mice with insufficient cardiolipin absorbed significantly more glucose from their bloodstream. However, their muscles weren’t primarily using this extra sugar for energy.
Instead, experiments with specially labeled glucose showed that muscle cells redirected the sugar to make their own antioxidants. This helped protect them from the harmful effects of excess ROS.
“Fiber switching is not muscle failure, but an exchange of muscle power for protection. This is also why any interference can have the opposite effect: when we gave the mice antioxidants to mop up ROS, their muscles did worse, not better,” says first author and co-correspondent Assistant Professor Fabian Finger from the University of Copenhagen.
A potential new approach to treating muscle wasting
Although the results suggest possible treatments for age-related muscle decline, 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.
However, researchers already have ways to influence cardiolipin.
The FDA recently granted accelerated approval to elamipretide, a drug designed to help stabilize cardiolipin, for Barth syndrome, a rare inherited disorder. This suggests that targeting the molecule is medically feasible, although its effectiveness against common age-related muscle loss remains unknown.
Another potential target for treatment is ERRγ, the protein responsible for helping muscles adapt to mitochondrial stress.
ERRγ belongs to a family of proteins called nuclear receptors. These proteins are already established targets for about 10 to 15 percent of FDA-approved drugs made from small molecules. Drugs that activate ERRγ are also being investigated preclinically for other medical applications.
The results suggest that future therapies may work by restoring cardiolipin levels or influencing protective adaptations controlled by ERRγ.
“What encourages me most is that even partial recovery of cardiolipin was sufficient to bring 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,” says lead author Zachary Gerhart-Hines, associate professor at the NNF Center for Basic Metabolic Research at the University of Copenhagen.
The research involved scientists from more than 20 institutions. It was led by the NNF Center for Basic Metabolic Research at the University of Copenhagen in collaboration with the Center for Adipocyte Signaling at the University of Southern Denmark.
Financial support came from the Novo Nordisk Foundation, the European Research Council, the Lundbeck Foundation, the US National Institutes of Health and other funding agencies.
Gn Health
