A new study from the Salk Institute suggests that a group of proteins called estrogen-related receptors (ERRs) may help fix problems with energy production in muscle cells, potentially offering new hope for people suffering from muscle fatigue and metabolic diseases.
The research, published in Proceedings of the National Academy of Sciences, shows that these receptors play a key role in how muscles create energy—especially during exercise. Scientists believe that by activating ERRs, they may be able to help people who struggle with low energy due to illness or aging.
What Are Estrogen-Related Receptors?
Estrogen-related receptors look similar to traditional estrogen receptors, but their job has remained largely unknown—until now. Researchers discovered that these receptors help control how many mitochondria (tiny energy-producing parts of our cells) are made in muscle tissue.
“Mitochondria are like power plants for our cells,” explained Ronald Evans, the study’s senior author and a professor at the Salk Institute. “Our muscles need a lot of energy to move, especially during exercise. ERRs help create that energy.”
Evans, who first identified nuclear hormone receptors back in the 1980s, said this new research shows ERRs are essential in helping muscles grow stronger and produce more energy.
Why This Matters
About 1 in 5,000 people are born with problems in their mitochondria. Many others develop energy issues later in life because of conditions like cancer, heart disease, multiple sclerosis (MS), or even aging. These issues can lead to extreme tiredness and weak muscles, which are hard to treat.
The new research offers hope that boosting ERRs could help restore energy in people who can’t exercise or have diseases that affect muscle strength.
“We know that exercise triggers the creation of more mitochondria,” said Weiwei Fan, the study’s lead author. “But for people too sick or weak to exercise, we’re looking for ways to trigger that same response through medicine.”
How the Study Worked
The research team studied mice to see how three types of ERRs—alpha, beta, and gamma—affect muscle cells. When they removed just the alpha version (the most common one), the effect on the muscles was small. But when they removed both alpha and gamma, the muscles showed serious problems in their ability to make energy.
To test whether ERRs are involved in the muscle’s response to exercise, the scientists had mice run on wheels. They found that mice without the alpha-type ERR could no longer increase their mitochondria after exercising, meaning the muscles couldn’t grow stronger in the usual way.
The team also looked at another protein called PGC1α, known as the “master switch” for making new mitochondria. However, PGC1α can’t work alone—it needs a partner to activate genes. The study found that PGC1α partners with ERRα to switch on the genes that boost mitochondrial growth. This makes ERRα a more promising target for future drugs, since it can directly influence gene activity.
What’s Next
Scientists at Salk plan to keep studying how ERRs work, especially the alpha and gamma types, to find better ways to treat diseases linked to poor energy metabolism.
The research was supported by several groups, including the National Institutes of Health, the U.S. Navy, and the Wu Tsai Human Performance Alliance.
Contributing Authors:
Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, Michael Downes (Salk); Tae Gyu Oh (Salk and University of Oklahoma); Christopher Liddle (University of Sydney, Australia)
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