How muscles lose strength with age

The key to the puzzle turned out to be cardiolipin, a special fatty molecule that is found almost nowhere in the cell except in the inner mitochondrial membrane. There, it is critically important: it maintains the unique folded structure of the membrane, without which mitochondria cannot properly generate energy and produce the metabolic signals and building blocks the cell needs. Researchers have found that with age and in the presence of disease, the level of cardiolipin in the mitochondria of muscle cells decreases, which causes the mitochondria themselves to become deformed and perform their functions less effectively. This applies to both mice and humans: a decrease in cardiolipin was also recorded in samples of human muscle tissue.

To understand whether the decline in cardiolipin is the cause of the changes rather than their consequence, scientists artificially reduced its levels in young mice so that the pattern resembled age‑related changes. As a result, the animals experienced the same shift from fast‑twitch to slow‑twitch muscle fibers that is usually observed in older individuals. And when the level of cardiolipin was partially restored, to about two‑thirds of the normal level, the processes of muscle depletion began to reverse, and the premature death of the animals was completely prevented.

It turned out that when the level of cardiolipin drops, overloaded mitochondria begin to produce much more reactive oxygen species (ROS) — molecules that can damage cells. But in this case, ROS also act as an alarm signal. When researchers used an antioxidant to remove ROS in cells with low cardiolipin, the transition to slow‑twitch fibers noticeably weakened. That is, the body uses the increase in ROS as a signal to undergo restructuring.

The switch itself works via the ERRγ protein; it triggers mitochondrial restructuring and a switch in fiber type from fast to slow in cells. If ERRγ is blocked in a culture of muscle cells, the fiber type switch is completely stopped.

Reorganized slow fibers better protect the cell from ROS due to the way they manage glucose. In mice with cardiolipin deficiency, muscles took up sugar from the blood more actively, but not to burn it for energy. Using labeled sugar, experts traced that it was used to produce the body’s own cellular antioxidants. It turns out that the muscle deliberately sacrifices power for the sake of protection.

It is especially important that simply suppressing ROS with antioxidants can be harmful. According to Fabian Finger, one of the authors of the study, when mice were given antioxidants to remove reactive oxygen species, their muscle condition did not improve but worsened.

The study was conducted on mice, and human samples were used only to confirm that cardiolipin actually decreases with age. Nevertheless, there are already options for what can be targeted. For example, the drug elamipretide, which is believed to stabilize cardiolipin, has received accelerated FDA approval for the treatment of a rare genetic disorder — Barth syndrome.

According to the authors, the fact that even partial restoration of cardiolipin levels was sufficient to significantly improve muscle condition is particularly encouraging. Now the main question is whether it is possible to increase the level of cardiolipin in aging muscle or to influence ERRγ in such a way as to stimulate beneficial adaptations. This is precisely where the scientists see the main therapeutic potential of the work.