Aging Muscles May Trade Strength for Protection, Mouse Study Finds

Muscle is not one uniform tissue. It is bundles of fibers with different jobs, and a study from the University of Copenhagen has found that the way those fibers change with age may be a defense rather than a collapse.

Fast-twitch fibers deliver powerful, rapid movement but tire quickly. Slow-twitch fibers support sustained activity and carry more mitochondria, the structures that produce much of a muscle's energy. As people age, strength declines and mitochondria become less efficient. Yet aging muscle also ends up with a larger share of slow-twitch fibers, even though those fibers lean hardest on the mitochondria that are faltering. Similar shifts appear in several conditions that cause muscle wasting. The researchers set out to explain why muscle would rely more on an energy system that is working less well.

They focused on cardiolipin, a fat molecule found almost exclusively in the inner membrane of mitochondria, where it helps preserve the membrane's folded structure. Without enough of it, mitochondria produce less energy and make fewer of the chemical signals and materials cells need. The team found that cardiolipin levels fall in muscle mitochondria from both mice and humans as they age or develop disease, alongside structural abnormalities and loss of normal function.

To test whether the loss causes these changes rather than merely accompanying them, the researchers lowered cardiolipin in young mice. The muscles resembled those of naturally aged animals, with fibers moving from fast-twitch toward slow-twitch, the same pattern seen in older mice and people. When cardiolipin was restored to roughly two-thirds of its normal level, muscle wasting began to reverse, and the premature deaths seen in the affected mice were completely prevented.

Further experiments pointed to the fiber switch as protective. With less cardiolipin, 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 trigger the change from fast to slow fibers. Treating cardiolipin-deficient muscle cells with an antioxidant made the transformation less pronounced. A protein called ERRγ coordinates the response, directing cells to reorganize their mitochondria and alter fiber traits. When it was inhibited in lab-grown muscle cells, the fiber-type transition stopped entirely.

The mice also showed how the remodeled fibers defend themselves. Animals with too little cardiolipin pulled considerably more glucose from their blood, but their muscles were not mainly burning it for energy. Tracking specially labeled glucose, the team saw cells redirect it toward making their own antioxidants, shielding them from 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. He added that interfering can backfire: mice given antioxidants to mop up ROS had worse muscle outcomes, not better.

The caveats are plain. The protective mechanism and the reversal of wasting were shown in mice. Human muscle samples were used only to confirm that cardiolipin declines with age. Still, there are existing levers. The FDA recently granted accelerated approval to elamipretide, a drug meant to stabilize cardiolipin, for Barth syndrome, a rare inherited disorder, which suggests targeting the molecule is feasible. Whether it helps ordinary age-related muscle loss is unknown. ERRγ is a nuclear receptor, a protein family that is the target of about 10 to 15 percent of FDA-approved small-molecule drugs, and drugs that activate ERRγ are in preclinical research for other uses.

Senior author Zachary Gerhart-Hines, Associate Professor at the NNF Center for Basic Metabolic Research, said the most encouraging result was that even partial recovery of cardiolipin brought muscle back. The open question, he said, is whether cardiolipin can be raised in aging muscle or ERRγ targeted to promote healthy adaptation. The work involved scientists from more than 20 institutions, led by the Copenhagen center with the University of Southern Denmark's Center for Adipocyte Signaling, and was funded by the Novo Nordisk Foundation, the European Research Council, the Lundbeck Foundation, the US National Institutes of Health and others.