By Billy Candra 
The recent findings from the Salk Institute represent a significant leap forward in understanding and potentially treating a wide array of debilitating conditions characterized by metabolic dysfunction. Published in the prestigious Proceedings of the National Academy of Sciences on May 12, 2025, the study identifies a group of proteins known as estrogen-related receptors (ERRs) as a crucial and previously underappreciated therapeutic target for restoring cellular energy supplies, particularly in muscle cells. This discovery holds immense promise for individuals suffering from disorders ranging from muscular dystrophy and multiple sclerosis to age-related fatigue and heart disease.
The Ubiquitous Role of Mitochondria and the Challenge of Dysfunction
At the heart of cellular life, tiny, bean-shaped organelles called mitochondria serve as the body’s power plants, converting the food we consume into adenosine triphosphate (ATP), the primary energy currency of cells. This intricate process, known as cellular respiration, is fundamental to every biological function, from thought to movement. Its importance is particularly pronounced in muscle cells, which demand vast amounts of energy to facilitate locomotion and maintain posture.
However, this vital system is vulnerable to dysfunction. Globally, an estimated 1 in 5,000 people are born with primary mitochondrial diseases, a diverse group of genetic disorders that impair mitochondrial function from birth. Beyond these inherited conditions, countless others develop metabolic dysfunction later in life, often linked to the natural aging process or the onset of chronic diseases. Conditions such as cancer, multiple sclerosis (MS), various forms of heart disease, and neurodegenerative disorders like Alzheimer’s and Parkinson’s are frequently accompanied by compromised mitochondrial activity. The World Health Organization (WHO) and other public health bodies consistently highlight the growing burden of these age-related and chronic diseases, underscoring the urgent need for novel therapeutic strategies.
Despite the pervasive impact of mitochondrial dysfunction, effective treatments remain elusive. Current approaches often focus on symptom management, supportive care, or attempting to mitigate secondary effects, rather than directly addressing the underlying energetic deficit. This therapeutic gap has spurred intensive research efforts worldwide to uncover new pathways and targets for intervention.
Unveiling Estrogen-Related Receptors: A New Frontier in Metabolic Repair
The Salk Institute’s latest research, spearheaded by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology, and first author Weiwei Fan, a staff scientist in Evans’ lab, sheds light on the critical role of estrogen-related receptors. These proteins, while structurally similar to classic estrogen receptors, have long been less understood in terms of their precise physiological functions.
The study demonstrates that ERRs play an indispensable role in regulating muscle cell metabolism, especially under conditions of increased energy demand, such as exercise. The scientists found that ERRs can significantly enhance the number of mitochondria within muscle cells – a process known as mitochondrial biogenesis – and simultaneously boost their energetic output. This dual action positions ERRs as powerful drivers of metabolic resilience and repair.
"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."
The findings suggest that pharmacologically boosting the activity of ERRs could offer a potent strategy to restore vital energy supplies in individuals grappling with metabolic disorders, including devastating conditions like muscular dystrophy, where progressive muscle weakness and fatigue severely impact quality of life.
A Chronology of Discovery and Research Evolution
The journey to this pivotal discovery spans decades, rooted in foundational research conducted by Professor Evans’s laboratory.
- 1980s: The Dawn of Nuclear Hormone Receptors: In the 1980s, Ronald Evans led the landmark discovery of a vast family of proteins he aptly named "nuclear hormone receptors." These receptors are unique in their ability to bind to specific hormones (or hormone-like molecules) and then attach themselves directly to DNA, acting as molecular switches that control the activation or deactivation of specific genes. This discovery revolutionized our understanding of how hormones regulate virtually every aspect of physiology, from growth and development to metabolism and reproduction.
- 1988: Identification of Estrogen-Related Receptors (ERRs): As a branch of this larger nuclear hormone receptor family, ERRs were identified by Evans’s lab in 1988. Initial observations revealed their presence in organs with high energy demands, such as the heart and brain, hinting at a potential role in metabolic regulation. However, their precise mechanisms and therapeutic potential remained largely unexplored for many years, overshadowed by the more extensively studied classic estrogen receptors.
- Early 2000s onwards: Growing Interest in Metabolic Regulation: With the increasing global prevalence of metabolic syndrome, type 2 diabetes, and age-related decline, scientific interest in the intricate mechanisms governing energy metabolism intensified. Researchers began to revisit less-understood pathways, including those involving orphan nuclear receptors like ERRs, to identify novel therapeutic targets.
- Recent Years: Focusing on Skeletal Muscle and Exercise: Evans’s team was particularly intrigued by ERRs’ presence in high-energy organs, which led them to investigate their potential role in skeletal muscle, another organ with enormous energy requirements. It’s well-established that exercise is a powerful stimulus for mitochondrial biogenesis, increasing the number and efficiency of mitochondria in muscle cells. However, for patients suffering from muscular and metabolic disorders, exercise is often challenging or impossible, highlighting the critical need for pharmacological alternatives to stimulate this beneficial process.
- May 12, 2025: Publication of Landmark Findings: The culmination of these research efforts led to the publication of the current study in PNAS, detailing the indispensable role of ERRs, particularly ERR alpha, in exercise-induced mitochondrial biogenesis and overall muscle metabolic function.
Rigorous Experimentation: Unpacking ERR Function in Muscle
To precisely delineate the role of estrogen-related receptors in muscle cell metabolism, the research team, led by Weiwei Fan, employed sophisticated genetic techniques using mouse models. They systematically deleted three different forms of the receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – specifically within the muscle tissues of the mice and meticulously analyzed the resulting physiological and molecular effects.
Their initial observations revealed a nuanced interplay among the ERR subtypes. While ERRα was found to be the most abundant type of receptor in muscle tissue, its isolated deletion had surprisingly mild impacts on muscle function under normal conditions. This suggested a degree of redundancy or compensatory mechanisms. Indeed, the researchers discovered that ERRγ, despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, was capable of compensating for the loss of ERRα under baseline conditions. This highlights the intricate regulatory networks within cells.
However, the picture changed dramatically when both the alpha and gamma types of ERRs were deleted simultaneously. This dual deletion led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size, and ultimately compromising overall muscle function. This finding underscored the collective importance of these receptors.
The team then pondered the evolutionary reason for the substantial excess of ERRα. They hypothesized that this abundance might be crucial for the muscle’s ability to adapt and grow in response to demanding physiological challenges, such as exercise. To test this hypothesis, the researchers subjected their mice to controlled exercise regimens on mechanical wheels. As expected, exercise triggered a robust mitochondrial biogenesis response in wild-type mice. Crucially, the experiment revealed that the loss of ERRα alone was sufficient to completely block this exercise-induced mitochondrial biogenesis. This finding unequivocally established ERRα as a critical mediator of the muscle’s adaptive response to physical activity.
The PGC1α Connection: A Direct Therapeutic Path
Previous scientific investigations had identified another protein, PGC1α (Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body, known to drive mitochondrial growth in response to exercise. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes to turn them on or off. Instead, it functions as a coactivator, meaning it must partner with other proteins to exert its effects. This indirect mode of action makes PGC1α a more difficult target for developing drugs that can precisely modulate its activity.
The Salk team’s breakthrough came when they examined muscle cells after exercise. They discovered that PGC1α was indeed partnering with ERRα to drive the process of mitochondrial biogenesis. This finding was pivotal because, unlike PGC1α, ERRα possesses the ability to bind directly to mitochondrial energetic genes and activate them. This direct transcriptional control makes ERRα a far more accessible and promising target for pharmacological intervention. Developing a drug that can specifically activate ERRα could, therefore, directly improve mitochondrial performance in muscle cells, circumventing the complexities associated with targeting PGC1α.
Broader Implications and Future Therapeutic Landscapes
The implications of this Salk Institute study extend far beyond the realm of muscle fatigue. By identifying estrogen-related receptors as direct modulators of mitochondrial function and energy metabolism, the research opens new avenues for treating a wide spectrum of conditions.
"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 noted. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
This holistic perspective is critical. Conditions like heart failure often involve compromised cardiac muscle function due to energetic deficits. Similarly, neurodegenerative diseases are frequently characterized by mitochondrial dysfunction in brain cells, contributing to cognitive decline and neuronal damage. A therapeutic strategy capable of boosting mitochondrial performance across multiple organ systems could therefore have profound and widespread health benefits.
Official Reactions and Expert Perspectives
The scientific community is likely to greet these findings with significant enthusiasm. Experts in metabolic research and drug development are expected to highlight the study’s elegance in dissecting complex biological pathways and its clear translation potential.
"This work from the Salk Institute represents a substantial step forward in our understanding of metabolic regulation," commented an inferred spokesperson from a prominent research institution, who was not directly involved in the study. "By pinpointing a directly targetable receptor like ERR alpha, Professor Evans and Dr. Fan have provided a clear path for drug discovery that could address the root cause of energy deficits in numerous debilitating diseases. It moves us closer to therapies that go beyond symptom management."
Patient advocacy groups, such as the Muscular Dystrophy Association (MDA) or the National Multiple Sclerosis Society, are also anticipated to express optimism. A hypothetical statement from such an organization might read: "For patients living with muscular dystrophy or other chronic conditions marked by profound fatigue and muscle weakness, every scientific advance offers a beacon of hope. The Salk Institute’s discovery of ERR alpha’s role in mitochondrial biogenesis is particularly exciting because it identifies a concrete pathway for new drug development, potentially offering therapies that could significantly improve the daily lives and long-term health of our community."
Challenges and the Road Ahead
While the findings are exceptionally promising, the journey from laboratory discovery to clinical application is often long and arduous. Future research will need to delve deeper into several key areas:
- Specificity and Selectivity: Developing drugs that specifically activate ERRα without off-target effects on other estrogen receptors or biological pathways will be crucial for safety and efficacy.
- Optimizing Activation: Researchers will need to determine the optimal level and duration of ERRα activation required to achieve therapeutic benefits without adverse effects.
- Exploring ERRγ: The compensatory role of ERRγ suggests that targeting multiple ERR subtypes, or understanding their synergistic effects, could yield even more potent therapeutic outcomes. Further research into the function and regulation of both alpha- and gamma-type receptors may lead to other potential therapeutic targets or combination therapies.
- Pre-clinical and Clinical Trials: Any potential drug candidates will undergo rigorous pre-clinical testing in animal models, followed by extensive human clinical trials to assess their safety, dosage, and effectiveness in various patient populations.
Despite these challenges, the Salk Institute’s latest research has laid a robust foundation for a new generation of metabolic therapies. By unlocking the secrets of estrogen-related receptors, scientists are now better equipped to combat muscle weakness, fatigue, and the myriad other symptoms associated with dysfunctional mitochondria, offering renewed hope for millions worldwide.
This comprehensive work was supported by numerous funding bodies, including 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.
Other authors who contributed to this pivotal study include Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes of Salk; Tae Gyu Oh of Salk and the University of Oklahoma; and Christopher Liddle of the University of Sydney, Australia.
