Muscles naturally become weaker as we get older, but scientists have discovered that some of the changes associated with aging may actually help protect muscle cells from damage. New research reveals why aging muscles shift toward 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 fatigue relatively quickly. Slow-twitch fibers, by contrast, 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 depend heavily on the very mitochondria that are losing their ability to function. Researchers have observed similar changes in several conditions that cause muscle wasting.
This raises an important question: Why would muscles increasingly rely on an energy-producing system that is becoming less effective?
A Crucial Molecule Linked to Muscle Aging
To investigate this puzzle, scientists focused on cardiolipin, a specialized fat molecule located almost exclusively within the inner membrane of mitochondria. Cardiolipin helps maintain the membrane’s distinctive folded architecture, which is essential for proper mitochondrial activity.
When cardiolipin is lacking, mitochondria struggle to generate sufficient energy. They also become less capable of producing the chemical signals and essential materials that cells require to function.
The researchers discovered that cardiolipin levels decrease in muscle mitochondria from both mice and humans as they age or experience disease. This decline was accompanied by structural abnormalities in the mitochondria and a loss of normal function.
To determine whether reduced cardiolipin directly contributes to these changes, rather than simply occurring alongside them, the team experimentally lowered cardiolipin levels in young mice.
The results closely resembled what happens during natural aging. Muscle fibers shifted away from the fast-twitch type toward slow-twitch fibers, matching the pattern previously observed in older mice and humans.
Even more strikingly, restoring cardiolipin to approximately two-thirds of its normal concentration began reversing muscle wasting and completely prevented the premature deaths seen in the affected animals.
Why Aging Muscles Sacrifice Strength for Protection
Further experiments revealed an unexpected explanation for the transformation. Rather than representing only a breakdown in muscle function, the shift toward slow-twitch fibers appears to be a protective response.
When cardiolipin concentrations fall, damaged mitochondria produce much larger quantities of reactive oxygen species (ROS). These highly reactive molecules can harm cellular structures, but they also play an important role in signaling that something is wrong.
The researchers found that ROS help initiate the transition from fast-twitch 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 known as ERRγ plays a central role in coordinating this response. It directs cells to reorganize their mitochondria and change their muscle fiber characteristics. When scientists inhibited ERRγ in muscle cells grown in the laboratory, the transition between fiber types stopped entirely.
The team also discovered how the newly remodeled fibers help defend themselves.
Mice with insufficient cardiolipin absorbed considerably more glucose from their bloodstreams. However, their muscles were not primarily using this additional sugar to produce energy.
Instead, experiments that tracked specially labeled glucose showed that muscle cells redirected the sugar toward manufacturing their own antioxidants. This helped protect them against the damaging effects of 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,” says Assistant Professor Fabian Finger, first and co-corresponding author, from the University of Copenhagen.
A Potential New Approach to Treating Muscle Wasting
Although the findings point toward 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 decrease with age in people.
Nevertheless, researchers already have some ways to influence cardiolipin.
The FDA recently granted accelerated approval to elamipretide, a medication 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 ordinary age-related muscle loss remains unknown.
Another potential treatment target 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 approximately 10 to 15 percent of FDA-approved medications made from small molecules. Drugs that activate ERRγ are also being investigated in preclinical research for other medical applications.
The findings suggest that future therapies might work by restoring cardiolipin levels or by influencing the protective adaptations controlled by ERRγ.
“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,” says senior author Zachary Gerhart-Hines, Associate Professor at the NNF Center for Basic Metabolic Research, 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, European Research Council, Lundbeck Foundation, US National Institutes of Health, and additional funding organizations.