By Billy Candra 
A pioneering study from the Salk Institute has unveiled a critical role for a class of proteins known as estrogen-related receptors (ERRs) in the intricate process of energy metabolism and muscle function. Published in the Proceedings of the National Academy of Sciences on May 12, 2025, these findings suggest that targeting ERRs could represent a transformative new therapeutic strategy for a spectrum of debilitating conditions characterized by mitochondrial dysfunction and muscle fatigue, including muscular dystrophy, multiple sclerosis, heart disease, dementia, and age-related decline. This discovery not only deepens our understanding of cellular energy regulation but also opens promising avenues for drug development aimed at restoring vital energy supplies in affected individuals.
The Silent Scourge of Metabolic Dysfunction
At the heart of every cell, tiny, bean-shaped organelles called mitochondria serve as the body’s powerhouses, converting the food we consume into adenosine triphosphate (ATP), the primary energy currency of life. This cellular-level metabolism is particularly vital in high-energy demand tissues such as skeletal muscles, which require immense fuel to power movement, and the brain and heart, which operate continuously.
Unfortunately, mitochondrial dysfunction is a pervasive and challenging health issue. While approximately 1 in 5,000 individuals are born with primary mitochondrial diseases—a group of genetic disorders that severely impair mitochondrial function—millions more develop metabolic dysfunction later in life. This acquired dysfunction is intricately linked to the aging process and is a common hallmark of numerous chronic diseases. For instance, metabolic impairments contribute significantly to the pathology of neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, cardiovascular diseases, certain cancers, and autoimmune disorders such as multiple sclerosis (MS). Patients often experience debilitating muscle weakness, profound fatigue, and cognitive impairments, severely diminishing their quality of life. The global burden of these conditions underscores the urgent need for effective therapeutic interventions that can address the root cause of energy deficits.
A New Therapeutic Frontier: Estrogen-Related Receptors
The Salk Institute’s recent research brings a beacon of hope to this challenging landscape. The study meticulously demonstrates that estrogen-related receptors, a group of proteins often found in metabolically active tissues, play an indispensable role in maintaining and enhancing muscle cell metabolism. Specifically, scientists observed that ERRs are crucial for increasing both the number of mitochondria within muscle cells (a process known as mitochondrial biogenesis) and their energetic output, especially during periods of increased energy demand, such as exercise.
This revelation positions ERRs as a highly attractive therapeutic target. By developing drugs that can specifically boost the activity of these receptors, researchers envision a future where energy supplies can be effectively restored in individuals suffering from a range of metabolic disorders and muscle-wasting conditions. The potential impact spans from enhancing muscle strength and combating fatigue in muscular dystrophy patients to improving overall cellular function in the context of aging and chronic diseases.
A Legacy of Discovery: Professor Ronald Evans and Nuclear Hormone Receptors
The significance of this discovery is amplified by its deep roots in decades of foundational research led by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Professor Evans is a towering figure in the field of molecular biology, renowned for his landmark discovery in the 1980s of a family of proteins he termed "nuclear hormone receptors."
These receptors are molecular switches that, when activated by specific hormones or metabolic signals, bind directly to our DNA, controlling the "on" or "off" states of genes. This intricate regulatory mechanism underpins a vast array of physiological processes, from metabolism and development to inflammation and circadian rhythms. Evans’ pioneering work laid the groundwork for understanding how hormones exert their profound effects on the body at a genetic level, fundamentally transforming endocrinology and pharmacology.
It was within this broader family of nuclear hormone receptors that Evans’ laboratory first discovered estrogen-related receptors (ERRs) in 1988. While their structural resemblance to classic estrogen receptors was noted, their precise physiological functions remained less understood compared to their well-characterized counterparts. However, Evans’ team was among the first to recognize the potential involvement of ERRs in energy metabolism, a hypothesis that has now been robustly confirmed and significantly expanded by their latest findings. "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," Professor Evans explained. "Our lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism. Now we’ve learned that estrogen-related receptors are indispensable drivers 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 involve metabolic dysfunction."
Unraveling the Muscle’s Energy Engine
The Salk team’s focused investigation was driven by the observation that ERRs are abundantly present in tissues with high energy demands, such as the heart and brain. This led them to hypothesize a crucial role for ERRs in skeletal muscle, another organ system that constantly requires significant fuel, particularly during physical activity.
Exercise is a powerful natural stimulus for mitochondrial biogenesis. When muscles are challenged, cells respond by increasing the number and efficiency of their mitochondria to meet heightened energy requirements. However, for millions worldwide suffering from muscular and metabolic disorders, strenuous exercise is often impossible or counterproductive, creating a vicious cycle of deconditioning and declining health. This reality spurred the researchers to seek pharmacological alternatives that could mimic the beneficial effects of exercise. "Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," stated first author Weiwei Fan, a staff scientist in Evans’ lab. "This got us thinking — if we could understand how exercise induces mitochondrial biogenesis, we might be able to target those same mechanisms pharmacologically to trigger this process in people who are too weak to exercise."
To meticulously dissect the role of ERRs in muscle cell metabolism, Fan and his colleagues conducted a series of elegant experiments using mouse models. They genetically deleted three different forms of ERRs—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of mice and then meticulously analyzed the resulting physiological and cellular effects.
Their investigations revealed nuanced insights into the interplay of these ERR subtypes. While ERRα was found to be the most abundant receptor in muscle tissue, its isolated loss had surprisingly mild impacts under normal, unstressed conditions. Intriguingly, the researchers discovered that ERRγ, despite making up only a small fraction (around 4%) of the total ERRs, could effectively compensate for the absence of ERRα, maintaining mitochondrial function. However, the combined deletion of both ERRα and ERRγ led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size, underscoring the critical, redundant roles of these two subtypes.
The Indispensable Role of ERRα in Exercise Adaptation
The redundancy observed under normal conditions led the team to hypothesize that the sheer abundance of ERRα might be critical for the muscle’s ability to adapt and grow in response to physiological stress, such as exercise. To test this, they subjected their genetically modified mice to exercise regimens using mechanical wheels. This experimental setup allowed them to precisely assess whether ERRα was indeed involved in the exercise-induced mitochondrial biogenesis.
The results were striking and definitive: the loss of ERRα alone completely blocked the exercise-induced increase in mitochondrial numbers. This finding unequivocally established ERRα as an indispensable driver of the muscle’s adaptive response to physical activity, mediating the crucial expansion of its energy-generating infrastructure.
Previous research had identified another protein, PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body. PGC1α is known to activate mitochondrial biogenesis in response to exercise and other metabolic demands. However, a significant challenge with PGC1α as a direct drug target is its inability to bind directly to DNA to regulate gene expression. Instead, it functions as a coactivator, relying on partner proteins to execute its genetic commands. This indirect mechanism makes PGC1α a more complex and less amenable target for direct pharmacological intervention.
Overcoming Therapeutic Hurdles: Why ERRs are a Promising Target
The Salk team’s subsequent investigations provided a crucial piece of the puzzle. When they examined muscle cells after exercise, they observed that PGC1α was indeed partnering with ERRα to drive mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the inherent capability to bind directly to the DNA sequences of mitochondrial energetic genes and switch them "on." This direct transcriptional activation capacity positions ERRα as a far more attractive and actionable target for therapeutic drug development. By activating ERRα, scientists could potentially bypass the complexities of indirect coactivator mechanisms, directly stimulating the genes responsible for mitochondrial growth and function.
This distinction is profoundly important for the pharmaceutical industry. Developing small-molecule drugs that can directly modulate the activity of a nuclear hormone receptor like ERRα is a well-established paradigm in drug discovery, offering a clearer path from laboratory findings to clinical applications. The ability of ERRα to directly engage with the genetic machinery of the cell makes it an exceptionally promising candidate for restoring metabolic vigor.
Broader Implications and a Glimpse into the Future
The implications of this Salk Institute breakthrough extend far beyond skeletal muscle. "Our findings suggest that activating estrogen-related receptors could not only help fuel people’s muscles, but it could also have other beneficial effects across the whole body," Fan commented. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
Given that mitochondrial dysfunction is implicated in a wide array of systemic diseases, a therapeutic strategy that boosts ERR activity could have widespread benefits. For patients suffering from neurodegenerative diseases like Alzheimer’s, where energy deficits contribute to neuronal damage, or heart failure, where compromised cardiac muscle function is a hallmark, enhancing mitochondrial performance through ERR activation could represent a paradigm shift in treatment.
Potential Impacts:
- Muscular Dystrophy: For conditions like Duchenne muscular dystrophy, where progressive muscle degeneration leads to severe weakness and fatigue, an ERR-targeting drug could potentially slow disease progression and improve muscle function.
- Aging-Related Fatigue: As individuals age, mitochondrial function often declines, contributing to sarcopenia (age-related muscle loss) and general fatigue. ERR activators could help maintain energy levels and physical resilience in the elderly.
- Chronic Diseases: In diseases like MS, where fatigue is a primary and debilitating symptom, or heart disease, where cardiac muscle energy metabolism is often compromised, ERR modulators could offer symptomatic relief and potentially improve disease outcomes.
- Metabolic Syndrome: Improving overall energy metabolism could also have positive effects on conditions associated with metabolic syndrome, such as type 2 diabetes and obesity, by enhancing cellular energy expenditure and glucose utilization.
Expert Perspectives and Future Directions
The scientific community is likely to receive these findings with considerable enthusiasm. The Salk Institute, renowned globally for its contributions to biology and medicine, continues to push the boundaries of fundamental research. Experts in endocrinology, metabolism, and pharmacology will undoubtedly recognize the therapeutic potential of ERRs. Patient advocacy groups for muscular dystrophy, MS, and other related conditions will find new hope in these preclinical discoveries, eagerly anticipating the translation of this science into effective treatments.
The path from groundbreaking research to clinical application is often long and arduous, involving extensive preclinical development, rigorous clinical trials, and regulatory approvals. However, the clear mechanism of action and the direct druggability of ERRα provide a solid foundation for accelerating this process. Future research will undoubtedly focus on several key areas:
- Selective Modulators: Developing highly selective ERRα agonists that can maximize therapeutic benefits while minimizing potential off-target effects.
- Alpha vs. Gamma: Further exploring the nuanced functions and regulatory mechanisms of both ERRα and ERRγ, given their compensatory roles, to identify optimal therapeutic targets or combinations.
- Whole-Body Effects: Conducting comprehensive studies to evaluate the systemic benefits and potential side effects of ERR activation across different organ systems.
- Disease Models: Testing ERR-targeting compounds in various preclinical disease models to confirm efficacy and safety before human trials.
This latest discovery from the Salk Institute represents a significant stride forward in the quest to combat metabolic dysfunction and its debilitating consequences. By illuminating the critical role of estrogen-related receptors, Professor Evans’ team has not only expanded our understanding of cellular energy dynamics but also provided a tangible and highly promising target for developing new therapies that could profoundly improve the lives of millions worldwide.
Acknowledgements and Funding
The groundbreaking work detailed in this study was supported by a consortium of esteemed organizations dedicated to advancing biomedical research. These include the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), the Department of the Navy (N00014-16-1-3159), the Larry L. Hillblom Foundation, Inc. (2021-D-001-NET), the Wu Tsai Human Performance Alliance, the Henry L. Guenther Foundation, and the Waitt Foundation. The collaborative efforts of researchers Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk, alongside Tae Gyu Oh of Salk and the University of Oklahoma, and Christopher Liddle of the University of Sydney, Australia, were instrumental in the successful execution and publication of this pivotal research.
