A recent study from the Salk Institute has unveiled a promising new avenue for treating muscle fatigue and metabolic disorders: estrogen-related receptors (ERRs). These nuclear hormone receptors, long overshadowed by their classical counterparts, are now emerging as crucial regulators of cellular energy metabolism, particularly in muscle tissues.
Understanding the Mitochondrial Challenge
Mitochondria, often referred to as the powerhouses of the cell, convert food into usable energy. This function is especially vital in muscle cells, where energy demands spike during movement and exercise. Unfortunately, 1 in 5,000 people are born with mitochondrial disorders, and countless others experience metabolic decline due to aging, cancer, multiple sclerosis (MS), heart disease, or dementia.
Until now, therapies targeting mitochondrial dysfunction have remained limited. But the latest findings published in Proceedings of the National Academy of Sciences (May 12, 2025) highlight a new approach: activating ERRs to restore mitochondrial function and improve energy levels, even in patients too weak to exercise.
ERRs: A Forgotten Family with Powerful Potential
First discovered in the 1980s by Ronald Evans, a pioneer in nuclear hormone receptor research at Salk, ERRs structurally resemble estrogen receptors but have long remained poorly understood. However, recent evidence confirms their essential role in energy metabolism, particularly during exercise-induced mitochondrial biogenesis—the process by which cells increase their mitochondrial count in response to increased energy demands.
“We’ve learned that estrogen-related receptors are indispensable drivers of mitochondrial growth and activity in our muscles,” says Evans. “This makes them a very promising target to treat muscle weakness and fatigue associated with metabolic dysfunction.”
A Closer Look at ERRs in Muscle Metabolism
The Salk team, led by staff scientist Weiwei Fan, studied the effects of knocking out the three known types of ERRs—alpha, beta, and gamma—in the skeletal muscles of mice. While ERRα was the most abundant and its absence had mild effects alone, the simultaneous deletion of both ERRα and ERRγ led to severe impairments in mitochondrial activity, structure, and size.
This discovery prompted researchers to test ERRα’s role in exercise-driven mitochondrial biogenesis. Using mice that exercised on mechanical wheels, they found that loss of ERRα alone completely halted mitochondrial biogenesis, proving its critical role in energy adaptation.
Partnering with PGC1α for Mitochondrial Boost
Previous research has shown that PGC1α, a protein dubbed the “master regulator of mitochondrial function,” initiates mitochondrial biogenesis in response to exercise. However, PGC1α cannot directly bind DNA—instead, it partners with transcription factors like ERRs to activate key genes.
This study confirmed that ERRα directly partners with PGC1α to activate genes responsible for energy production. Because ERRα can bind directly to DNA, it provides a more accessible and druggable target than PGC1α, opening new doors for therapeutic development.
Therapeutic Implications: Beyond Muscle Health
By targeting ERRs, researchers hope to mimic the effects of exercise in people who suffer from conditions such as muscular dystrophy, chronic fatigue, and metabolic disorders—individuals often too weak to engage in physical activity. Importantly, because ERRs are also active in high-energy-demand tissues like the heart and brain, the benefits could extend well beyond muscle health.
“Activating ERRs could help fuel muscles, but also support the brain, heart, and other organs affected by mitochondrial dysfunction,” says Fan.
Future Directions and Broader Impact
The findings not only reinforce the therapeutic promise of ERRs but also highlight the importance of understanding mitochondrial regulation at a molecular level. Ongoing research at the Salk Institute will further explore the distinct roles of ERRα and ERRγ, which may lead to the development of targeted therapies for a wide range of energy-deficient diseases.
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