The University of Valencia is taking part in a study that reveals the hidden mechanism behind one of the paradoxes of muscle ageing

Human muscles are made up of bundles of fibres. Some are fast-twitch fibres, optimised for short, powerful bursts of effort but quick to fatigue. Others are slow-twitch fibres, designed for endurance and containing greater numbers of mitochondria, the structures commonly known as the powerhouses of the cell.

“As we age, our muscles become weaker and the mitochondria they contain function less efficiently. At the same time, however, muscle composition tends to shift towards slow-twitch fibres, which are the most dependent on mitochondria. A similar change is observed in many diseases that cause muscle atrophy. It is paradoxical: why would ageing muscle become more dependent precisely on the machinery that is failing?”, asks Marta Moreno Torres, a Ramón y Cajal researcher at the UV, who is also affiliated with the research group of the Biomedical Research Networking Centre in Hepatic and Digestive Diseases (CIBEREHD, CB06/04/0081).

To unravel this mystery, the researchers – from more than 20 institutions – focused their attention on cardiolipin, a lipid molecule found almost exclusively in the inner membrane of mitochondria, where it is essential for maintaining the membrane’s characteristic folded structure. Without it, mitochondria are unable to produce sufficient energy or to generate the metabolic signals and building blocks that cells need.

The research team, led by Zach Gerhart-Hines (University of Copenhagen), discovered that cardiolipin levels decrease with age in skeletal muscle in both mice and humans, causing mitochondria to become deformed and function improperly. Marta Moreno Torres’s contribution focused on lipidomic analysis of skeletal muscle and, in particular, on identifying and quantifying the different cardiolipin species. These analyses made it possible to characterise which lipid species are involved in this decline, providing key evidence linking the loss of cardiolipin to muscle alterations associated with ageing.

To determine whether the reduction in cardiolipin was a cause rather than a consequence, the scientists lowered the levels of these lipids in young mice, thereby replicating the decline observed during ageing. They observed the same transition from fast-twitch to slow-twitch fibres that occurs naturally in older mice and humans. When cardiolipin levels were partially restored – to approximately two-thirds of normal levels – muscle atrophy began to reverse and premature death of the animals was completely prevented.

Why do muscles respond in this way? The answer proved surprising: it is a defence mechanism. As cardiolipin levels decline, stressed mitochondria produce much greater quantities of reactive oxygen species (ROS), which can damage cells. However, ROS also act as cellular signals: when the researchers used an antioxidant to eliminate ROS in muscle cells with reduced levels of cardiolipin, the transition to slow-twitch fibres was attenuated.

This change is mediated by a protein called ERRγ, which prompts cells to remodel their mitochondria and transform fibre type from fast-twitch to slow-twitch. When the scientists blocked ERRγ in muscle-cell cultures, this fibre transformation was completely halted. The slow-twitch fibres resulting from this remodelling are better equipped to protect cells against oxidative stress because of the way they use glucose. Mice with reduced cardiolipin levels took up more glucose from the bloodstream, but instead of using it primarily to produce energy, they diverted it towards metabolic pathways that strengthen the cell’s antioxidant defences.

Study in mice and a promising target

The study was conducted in mice, but human samples were used to confirm that cardiolipin levels also decline with age in humans. However, it is already possible to intervene in relation to cardiolipin: the FDA recently granted accelerated approval to elamipretide – a drug designed to stabilise cardiolipin – for the treatment of Barth syndrome, a rare genetic disorder.

ERRγ is also a promising target. It belongs to a class of molecules known as nuclear receptors – which are targeted by between 10 and 15% of all FDA-approved small-molecule drugs – and ERRγ activators are already in preclinical development for other indications.

Photo caption: Marta Moreno Torres, a researcher in the Department of Biochemistry and Molecular Biology at the UV, who is also affiliated with the research group of the Biomedical Research Networking Centre in Hepatic and Digestive Diseases (CIBEREHD CB06/04/0081).