Human muscles contain different types of fibres. Fast-twitch fibres support short, powerful movements but fatigue quickly, while slow-twitch fibres are built for endurance and contain more mitochondria, the structures responsible for producing energy.

As people age, muscles generally become weaker and mitochondrial function declines. At the same time, muscle composition tends to shift toward slow-twitch fibres, which rely heavily on mitochondria. Researchers set out to understand why aging muscles become more dependent on cellular machinery that is also becoming less efficient.

An international research team led by Zach Gerhart-Hines at the University of Copenhagen focused on cardiolipin, a specialized lipid found mainly in the inner membrane of mitochondria. This molecule helps maintain mitochondrial structure and supports the production of energy and important metabolic signals.

The researchers found that cardiolipin levels decrease with age in skeletal muscle in both mice and humans. This reduction was associated with changes in mitochondrial structure and function. Marta Moreno Torres of the University of Valencia contributed to the study by analyzing muscle lipids and identifying different cardiolipin species involved in the aging-related decline.

To determine whether reduced cardiolipin contributes directly to muscle aging, the scientists lowered its levels in young mice. The animals developed a shift from fast-twitch to slow-twitch muscle fibres similar to the changes seen during natural aging. When cardiolipin levels were partially restored, muscle wasting began to improve and premature death was prevented in the mice.

The researchers found that this muscle-fibre shift may represent a protective response. Reduced cardiolipin caused stressed mitochondria to produce more reactive oxygen species (ROS). Although excessive ROS can damage cells, they can also act as signals that trigger protective adaptations.

A protein called ERRγ was found to play a key role in this process. It helps regulate mitochondrial remodeling and promotes the transition from fast-twitch to slow-twitch fibres. When researchers blocked ERRγ in muscle cells, the fibre transformation was prevented. The resulting slow-twitch fibres were better equipped to manage oxidative stress by redirecting glucose toward pathways that strengthen antioxidant defenses.

The study was primarily conducted in mice, while human muscle samples were used to confirm that cardiolipin levels also decline with age. The findings point to cardiolipin and ERRγ as potential targets for future approaches to maintaining muscle function during aging.

Cardiolipin can already be targeted pharmacologically. The drug elamipretide, which stabilizes cardiolipin, has received accelerated FDA approval for treating Barth syndrome. ERRγ is also being investigated as a potential drug target, with activators already in preclinical development for other conditions.

Source: https://www.uv.es/uvweb/uv-news/en/news/university-valencia-is-taking-part-a-study-reveals-hidden-mechanism-one-paradoxes-muscle-ageing-1285973304159/Novetat.html?id=1286504694239&plantilla=UV_Noticies/Page/TPGDetaillNews