Scientists have identified a hidden mechanism behind why muscles weaken with age, revealing that the shift toward slower, less powerful muscle fibers is actually a protective strategy rather than a simple sign of decay. The research, led by the NNF Center for Basic Metabolic Research at the University of Copenhagen, shows that this transformation helps shield cells from damage caused by failing energy producers.
Cardiolipin Decline Drives Fiber Shift
Muscle tissue contains bundles of fibers with distinct functions. Fast-twitch fibers generate rapid, powerful movements but fatigue quickly. Slow-twitch fibers support sustained activity and rely heavily on mitochondria, the cellular structures that produce energy. As people age, muscle strength naturally declines and mitochondria become less efficient. Despite this, aging muscles develop a greater proportion of slow-twitch fibers, even though these fibers depend on the very mitochondria that are losing function.
To understand this paradox, researchers focused on cardiolipin, a specialized fat molecule located in the inner membrane of mitochondria. Cardiolipin maintains the membrane’s folded architecture, which is essential for proper activity. The team found that cardiolipin levels decrease in muscle mitochondria from both mice and humans as they age or experience disease. This decline is accompanied by structural abnormalities and a loss of normal function.
When scientists experimentally lowered cardiolipin levels in young mice, the results mimicked natural aging. Muscle fibers shifted away from the fast-twitch type toward slow-twitch fibers. Strikingly, restoring cardiolipin to approximately two-thirds of its normal concentration began reversing muscle wasting and completely prevented premature deaths in the affected animals.
ERR Protein Coordinates Protective Response
The transformation appears to be a deliberate protective response. When cardiolipin concentrations fall, damaged mitochondria produce larger quantities of reactive oxygen species (ROS). These molecules can harm cellular structures but also serve as signals 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 ERR plays a central role in coordinating this response. It directs cells to reorganize their mitochondria and change their muscle fiber characteristics. When scientists inhibited ERR in muscle cells grown in the laboratory, the transition between fiber types stopped entirely. The newly remodeled fibers help defend themselves by absorbing more glucose from the bloodstream. Instead of using this sugar for energy, muscle cells redirect it toward manufacturing their own antioxidants to protect against excess ROS.
Assistant Professor Fabian Finger, first and co-corresponding author from the University of Copenhagen, explained the trade-off. “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,” Finger said.
Although the experiments demonstrating the protective mechanism and reversal of muscle wasting were conducted in mice, human muscle samples confirmed that cardiolipin levels also decrease with age in people. This suggests that targeting the molecule is medically feasible. The FDA recently granted accelerated approval to elamipretide, a medication designed to stabilize cardiolipin, for Barth syndrome, a rare inherited disorder. Another potential treatment target is ERR, which belongs to a family of nuclear receptors that are already targets for approximately 10 to 15 percent of FDA-approved small molecule medications.
Senior author Zachary Gerhart-Hines, Associate Professor at the NNF Center for Basic Metabolic Research, University of Copenhagen, emphasized the therapeutic potential. “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 ERR to promote healthy adaptations. This is where the therapeutic potential lies,” Gerhart-Hines said.
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.
Source: ScienceDaily
