Estrogen-related receptors could be a key to repairing energy metabolism and muscle fatigue

A new study into Salk Institute suggests that estrogen -related receptors can be a key to restore energy metabolism and muscle fatigue.

Over the body, small bean -shaped structures called Mitochondria change the food that we eat on usable energy. This metabolism on a cellular level is especially important in muscle cells, which require a lot of fuel to provide our movement. 1 in 5,000 people, however, are born with dysfunctional mitochondria, and many others develop metabolic dysfunction later in life in conjunction with aging or diseases such as cancer, multiple sclerosis (MS), heart disease and dementia.

Mitochondrial dysfunction is difficult to treat, but recent findings from the SALK Institute show that a group of proteins called estrogen -related receptors could be a new and effective therapeutic target. The scientists discovered that estrogen -related receptors play an important role in muscle cell metabolism, especially during exercise. If our muscles need more energy, estrogen -related receptors can increase the number of mitochondria and improve their energetic output in muscle cells.

The findings published in Proceedings of the National Academy of Sciences On May 12, 2025, the development of a drug to stimulate estrogen -related receptors could be a powerful way to restore energy supply in people with metabolic disorders, such as muscular dystrophy.

Estrogen -related receptors are very similar to classic estrogen receptors, but their function is much less understood. Our lab discovered estrogen -related receptors in 1988 and was one of the first to recognize their role in energy metabolism. Now we have learned that estrogen -related receptors are indispensable Directors of mitochondrial growth and activity in our muscles. This makes them a really promising target to treat muscle weakness and fatigue in many different diseases that metabolic dysfunction entails. “

Ronald Evans, senior author, professor and chairman of March of Dimes in Molecular and Developmental Biology at Salk

In the 1980s, Evans led the milestone discovery of a family of proteins that he called “nuclear hormone receptors.” These hormone-activated receptors attach to our DNA and control which genes are switched on “or” off “.

Estrogen -related receptors are a branch of this family. They are often found in parts of the body that need a lot of fuel to function, such as the heart and brain. This inspired the Evans team to investigate their potential role in regulating metabolism in another energetic body: skeletal muscle.

Muscles require a lot of energy, especially when we train. Exercise is even one of the most important muscles for muscles to activate mitochondrial biogenesis, with a cell increasing the number of mitochondria to produce more fuel. But exercising is difficult for people with muscular and metabolic disorders, so scientists are looking for a different way to stimulate this process.

“Mitochondria are the energy factories of our cells, so the more we train, the more mitochondria our muscles need,” says first author Weiwei Fan, a staff scientist in Evans’s lab. “This put us on thinking and we could understand how exercise of mitochondrial biogenesis induce, we may be able to focus pharmacologically on the same mechanisms to activate this process in people who are too weak to practice.”

To determine whether estrogen -related receptors played a role in muscle cell metabolism, fan and his colleagues removed three different forms of the receptors (Alfa, Bèta and Gamma) in the muscle tissues of mice and investigating the resulting effects.

They discovered that although the most common type of receptor was the alpha receptor, loss of only this one receptor had mild consequences for muscle tissue. Moreover, the researchers discovered that although they only expressed 4% of the total estrogen-related receptors, the Gamma receptor was able to compensate for the loss of Alfa receptor under normal circumstances. If both alpha and gamma types were removed, this led to severe limitations in muscle mitochondrial activity, form and size.

So why is there so much too much about the estrogen-related receptor of the Alfa type (ERRA)? Suppose that the answer is to help muscles adapt and grow in response to exercise, the team had their mice practice on mechanical wheels. This exercise caused mitochondrial biogenesis, so that the researchers could assess whether ERRα was involved in the process. This experiment revealed that losing Errα could completely block mitochondria-biogenesis induced by effort.

Earlier studies showed that exercise -induced mitochondrial growth was driven by another protein that PGC1α is known as the main regulator of Mitochondria throughout the body. The problem is that unlike nuclear hormone receptors such as ERs, PGC1α does not directly bind to genes, so it trusts partner proteins to get the job done. This indirect effect makes PGC1A a more difficult target for the development of therapeutic medicines.

When Evans’s lab looked at the muscle cells after exercising, they discovered that PGC1A worked with Erra to stimulate mitochondrial biogenesis. But unlike PGC1α, Erra can immediately bind to mitochondrial energetic genes and “turn on” them, making it a promising target for improving the mitochondrial performance of Muscle.

“Our findings suggest that activating estrogen -related receptors can not only help feed the muscles of people, but it can also have other beneficial effects all over the body,” says Fan. “Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and the heart.”

Insight into how estrogen -related receptors function in muscle cells creates new opportunities to treat all parts of the body that are influenced by mitochondrial dysfunction. Future research will continue to investigate the function and regulation of both alpha and gamma-type receptors, which can lead to other potential therapeutic goals.

Other authors are Hui Wang, Lillian Crossley, Mingxiao HE, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins and Michael Downes van Salk; Tae Gyu Oh van Salk and the University of Oklahoma; And Christopher Liddle from the University of Sydney, Australia.

The work was supported by the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 from the Nav4195, PA014195, PA014195, the CA014195, the CA014195, P3014195, the Nav4195 CA014195, the CA014195, CA014195, the Nav4195868686868686868686868686814195614195141956141914191419141914141414141414141419s Department. De Navy. (N00014-16-1-3159), Larry L. Hillblom Foundation, Inc. (2021-D-001-Net), Wu Tsai Human Performance Alliance, Henry L. Guenther Foundation and Waitt Foundation.