The hidden switch behind one of the biggest paradoxes in aging muscle
Scientists in the Gerhart-Hines Group pinpoint a molecular cause of muscle aging, and a possible fix. By investigating how muscles adapt to age and disease-related decline, the scientists discovered the involvement of a druggable nuclear receptor, ERRγ, that could be targeted to preserve muscle function. The findings were published in Nature Aging.
Our muscles are built from bundles of fibers, much like a rope made of many smaller strands. Some of these fibers are so-called fast twitch, tuned for quick, powerful bursts of effort but quick to tire. Others are slow twitch, built for endurance rather than power. Part of what makes slow-twitch fibers so fatigue-resistant is that they are packed with more mitochondria, the structures colloquially known as the ‘powerhouses of the cell.’
As we age, our muscles grow weaker and lose function. However, our muscle fibers actually shift toward the slow-twitch type that is supposed to be fatigue-resistant. A similar shift occurs in many diseases that cause muscle wasting. Given that these should be the ‘tougher’ fibers, why does this change in composition not protect against the decline in muscle function? And can we do anything about it? These were the questions driving a team of researchers at the University of Copenhagen.
“We have found that the fiber switch is not the muscle failing, but the muscle trading power for protection. This is a new window into how muscle fundamentally ages, not just as a steady decline, but how and why it adapts the way it does. Understanding that logic is what lets us start asking where we can intervene or reverse elements, rather than simply watch the deterioration happen,” says Fabian Finger, first and co-corresponding author, who carried out the studies at the NNF Center for Basic Metabolic Research but has since started his independent research group at the Department of Biomedical Sciences, also located at the University of Copenhagen.
Tracing the fault to a single molecule
To understand the enigma, the researchers turned to a molecule that sits at the heart of nearly every function and structure inside mitochondria: cardiolipin, a fat molecule found essentially nowhere else in the cell. Mitochondria have two membranes, like a balloon within a balloon. Cardiolipin is located in the inner membrane and is essential for its unique folded structure. Without it, mitochondria are unable to produce enough energy or metabolic signals and building blocks that are critical for cells to function.
The researchers found cardiolipin levels decline in mouse and human muscle mitochondria with age and disease. As this happens, the mitochondria become distorted and unable to operate properly. But many things change in our muscles and bodies as we age, so how could the team be sure that falling cardiolipin was a cause of the problem, rather than simply a consequence of it?
To find out, the scientists lowered cardiolipin levels in young mice to mimic the drop seen in aging. They saw the identical fast-to-slow-twitch shift in muscle fibers that occurs naturally in aged mice and humans. The researchers also found that when cardiolipin levels were partially recovered to roughly two-thirds of normal, the muscle wasting began to reverse, and the animals’ early deaths were prevented entirely. These findings told them that cardiolipin loss was driving the shift.
So why would muscles with damaged, cardiolipin-depleted mitochondria respond by building more fibers that are especially rich in mitochondria? The answer was surprising: it’s a defense mechanism.
Damage that doubles as a signal
As cardiolipin levels decline, mitochondria are strained to produce energy and end up generating far more reactive oxygen species (ROS), which damage cells. But ROS is also a signal. When the researchers used an antioxidant to mop up ROS in cardiolipin-depleted muscle cells, the shift toward slow-twitch fibers was blunted, suggesting that ROS is itself part of the message.
That message reaches a protein called ERRγ, which triggers the cells to remodel their mitochondria and change fiber type from fast to slow twitch. When the scientists blocked ERRγ in cultured muscle cells, the fiber switch was completely shut down. A separate study of human muscle found that ERRγ is among the genes most strongly switched on in skeletal muscle during healthy aging.
The remodeled slow twitch fibers better protect the cell from ROS because of what they do with sugar. Cardiolipin-deficient mice pulled much more glucose out of the bloodstream, but not to burn for energy. By tracing labeled sugar through the muscle, the researchers showed it was instead used to manufacture the cell's own antioxidants, which neutralize ROS. So, the fiber switch from power to endurance is not the muscle failing, but a protection from aging.
The road to a treatment
The work was carried out in mice, and the human samples served only to confirm that cardiolipin also declines with age in people. However, the contribution of disrupted cardiolipin to human disease has been well-established for decades in Barth syndrome, a rare genetic disorder. Moreover, the FDA recently granted accelerated approval to elamipretide (sold as Forzinity), a drug proposed to stabilize cardiolipin, for Barth syndrome, suggesting that cardiolipin biology can be targeted therapeutically.
Exactly how the loss of cardiolipin is relayed to ERRγ remains unresolved and is an actively investigated question for the researchers. However, activators of ERRγ are already in preclinical development for other indications, and there is reason for hope: ERRγ belongs to a class of molecules called nuclear receptors, which are targeted by roughly 10 to 15 percent of all FDA-approved small-molecule medications. Whether ERRγ will join that list of drug successes remains to be seen.
“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 Associate Professor Zach Gerhart-Hines from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen, and senior author of the study.
The study spanned more than 20 institutions, led by the NNF Center for Basic Metabolic Research at the University of Copenhagen with the Center for Adipocyte Signaling at the University of Southern Denmark. In addition to the Novo Nordisk Foundation, the work was funded by the European Research Council, the Lundbeck Foundation and the US National Institutes of Health, among others.
Read the paper in Nature Aging: ‘Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in ageing muscle via ERRγ’ [LINK]