LA JOLLA, CA – May 12, 2025 – In a discovery poised to revolutionize the treatment of metabolic disorders, scientists at the Salk Institute for Biological Studies have identified a crucial role for a group of proteins known as estrogen-related receptors (ERRs) in regulating energy metabolism and combating muscle fatigue. Published today in the prestigious Proceedings of the National Academy of Sciences, the groundbreaking study suggests that targeting these receptors could unlock a powerful new therapeutic avenue for a wide range of debilitating conditions, from muscular dystrophy to the metabolic dysfunctions associated with aging, cancer, multiple sclerosis (MS), heart disease, and dementia.
The research illuminates how these often-overlooked receptors act as indispensable drivers of mitochondrial growth and activity within muscle cells, particularly during periods of high energy demand like exercise. By enhancing the body’s natural capacity to produce energy at a cellular level, drugs designed to boost ERR activity could offer a lifeline to millions suffering from chronic fatigue and muscle weakness stemming from compromised metabolism.
The Energetic Engine: Understanding Mitochondrial Dysfunction
At the heart of cellular energy production are mitochondria, the tiny, bean-shaped organelles often dubbed the "powerhouses of the cell." These critical structures tirelessly convert the food we consume into adenosine triphosphate (ATP), the usable energy currency that fuels every biological process. This intricate cellular-level metabolism is especially vital in muscle cells, which demand an immense supply of energy to power our movements, from the subtlest twitch to strenuous physical exertion.
However, this finely tuned system is vulnerable to dysfunction. A staggering 1 in 5,000 individuals are born with inherited mitochondrial disorders, leading to severe and often life-limiting conditions. Furthermore, a much larger segment of the population develops metabolic dysfunction later in life. This acquired impairment is intimately linked with the natural process of aging, contributing to age-related decline in physical function and vitality. Beyond aging, mitochondrial dysfunction is a hallmark of numerous chronic diseases, including the relentless progression of certain cancers, the neurodegenerative effects of multiple sclerosis and dementia, and the pervasive damage seen in heart disease.
The consequences of compromised mitochondrial function are profound: chronic fatigue, muscle weakness, reduced exercise tolerance, and impaired organ function. Despite the widespread impact of these conditions, effective treatments for mitochondrial dysfunction remain elusive, representing a significant unmet medical need. Current therapeutic strategies often focus on managing symptoms rather than addressing the root cause, leaving many patients with limited options and a diminished quality of life. The Salk Institute’s latest findings offer a beacon of hope, pointing towards a novel and fundamentally different approach to restoring cellular energy balance.
A Chronological Quest: Decades of Discovery Pave the Way
The journey to understanding estrogen-related receptors began decades ago, rooted in the pioneering work of Salk Professor Ronald Evans, the senior author of the current study. In the 1980s, Evans led the landmark discovery of a vast family of proteins he aptly named "nuclear hormone receptors." These extraordinary proteins function as molecular switches, capable of binding to specific hormones and, in response, attaching themselves directly to our DNA. By doing so, they exert precise control over which genes within a cell are activated ("turned on") or suppressed ("turned off"), orchestrating a myriad of biological processes, including metabolism, development, and inflammation. This foundational work fundamentally reshaped our understanding of how hormones regulate cellular function and laid the groundwork for countless subsequent discoveries in endocrinology and pharmacology.
Estrogen-related receptors emerged as a distinct branch within this expansive nuclear hormone receptor family. Unlike their more widely known cousins, the classic estrogen receptors (which bind to the hormone estrogen), ERRs do not directly bind estrogen. Their function, therefore, remained less understood for many years, despite their structural resemblance. However, Evans’ lab was among the first to recognize the potential significance of ERRs, identifying their involvement in energy metabolism as early as 1988. This early insight was driven by the observation that ERRs are abundantly expressed in tissues with high energy demands, such as the heart and brain. These organs are voracious consumers of ATP, requiring a constant and robust supply of energy to maintain their complex functions.
This distribution naturally piqued the research team’s curiosity: if ERRs were so prevalent in the heart and brain, what role might they play in regulating metabolism in another high-energy organ – skeletal muscle? The prevailing understanding of muscle physiology emphasized the critical role of mitochondria in fueling contraction and adaptation. Exercise, for instance, is a potent stimulus for mitochondrial biogenesis, the process by which cells increase the number and efficiency of their mitochondria to meet heightened energy demands. However, for individuals grappling with muscular and metabolic disorders, the very act of exercise is often a significant, if not impossible, challenge. This creates a vicious cycle: compromised muscles need more mitochondria, but the primary way to get them (exercise) is inaccessible. This therapeutic gap highlighted an urgent need for pharmacological interventions 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," explains Weiwei Fan, a staff scientist in Evans’ lab and the first author of the study. "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." This crucial question set the stage for the meticulous experimental investigations that would ultimately unveil the indispensable role of ERRs.
Supporting Data: Unraveling the Molecular Mechanism
To definitively ascertain the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues embarked on a series of carefully designed experiments using genetically modified mouse models. The researchers focused on the three different forms of ERRs – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – which are expressed in muscle tissues. Their strategy involved selectively deleting these receptors, both individually and in combination, within the muscle cells of the mice, and then meticulously observing the physiological consequences.
The initial findings revealed a nuanced picture of ERR distribution and function. The alpha receptor (ERRα) was found to be the most abundant type of ERR in muscle tissue. Surprisingly, however, the loss of ERRα alone resulted in only mild impacts on muscle tissue under normal, non-exercising conditions. This suggested a degree of functional redundancy or compensatory mechanisms at play. Indeed, the researchers discovered that the gamma receptor (ERRγ), though making up only a small fraction (approximately 4%) of the total estrogen-related receptors, was capable of compensating for the absence of ERRα under these baseline conditions. This subtle interplay highlighted the complexity of the ERR system and hinted at specialized roles for each subtype.
The critical insights emerged when the researchers investigated the effects of deleting multiple ERR subtypes. When both the alpha and gamma types of receptors were removed from muscle cells, the consequences were severe and unequivocal. The mice exhibited profound impairments in muscle mitochondrial activity, indicating a significant drop in their ability to generate energy. Furthermore, the morphology of the mitochondria themselves was compromised, displaying abnormal shapes and sizes, which are characteristic indicators of dysfunctional organelles. This crucial experiment demonstrated that while ERRγ could compensate for ERRα under normal conditions, the combined absence of these two key players crippled the muscle’s energetic machinery.
To further elucidate the specific role of the highly abundant ERRα, the team hypothesized that its prevalence was designed to help muscles adapt and grow in response to physical activity. To test this, the mice were subjected to a regimen of voluntary exercise on mechanical wheels – a standard method to induce mitochondrial biogenesis in animal models. This exercise regimen triggered a robust increase in mitochondrial numbers and activity in control mice, as expected. However, in the mice lacking ERRα alone, the results were striking: the loss of this single receptor entirely blocked the exercise-induced mitochondrial biogenesis. This finding unequivocally established ERRα as a central and indispensable mediator of the muscle’s adaptive response to physical exertion. Without ERRα, the muscles simply could not ramp up their energy factories in response to the demand of exercise.
The Salk team’s work then delved into the molecular cascade governing this process. Previous studies had shown that exercise-induced mitochondrial growth was largely driven by another protein known as PGC1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha). PGC1α is widely recognized as a "master regulator" of mitochondria throughout the body, playing a pivotal role in their formation and function. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot directly bind to DNA and regulate gene expression on its own. Instead, it functions as a coactivator, meaning it must partner with other proteins to carry out its gene-regulatory functions. This indirect mode of action makes PGC1α a more complex and difficult target for the design of small-molecule drugs, which typically aim to directly activate or inhibit a specific protein.
The Salk lab’s breakthrough came when they examined the muscle cells after exercise and discovered the crucial partnership. They found that PGC1α was indeed working in concert with ERRα to drive mitochondrial biogenesis. Crucially, however, unlike PGC1α, ERRα possesses the inherent ability to bind directly to the DNA sequences of mitochondrial energetic genes and turn them "on." This direct-binding capability positions ERRα as a far more accessible and promising target for therapeutic drug development. By activating ERRα directly, scientists could potentially bypass the complexities of PGC1α’s indirect action, offering a more straightforward path to improving muscle’s mitochondrial performance and overall energy supply.
Official Responses: Researchers Emphasize Transformative Potential
The significance of these findings resonated deeply with the research team. Senior author Ronald Evans, reflecting on decades of work, underscored the profound implications of the discovery. "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," says Evans, who also holds the March of Dimes Chair in Molecular and Developmental Biology at Salk. "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." His statement highlights the long arc of scientific inquiry, culminating in a clear understanding of ERRs’ critical role.
First author Weiwei Fan further elaborated on the potential systemic benefits of targeting ERRs. "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 explains. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." This perspective underscores the interconnectedness of cellular energy across the body, suggesting that a therapeutic intervention focused on muscle metabolism could yield widespread health improvements, combating fatigue and dysfunction in critical organs beyond just skeletal muscle.
The collaborative nature of the research was also a key theme, with a long list of contributors from Salk, the University of Oklahoma, and the University of Sydney, Australia. This multidisciplinary effort speaks to the complexity and scale of the investigation, bringing together diverse expertise to unravel a fundamental biological mystery.
Implications: A New Era for Metabolic Therapies
The Salk Institute’s discovery holds immense promise for transforming the landscape of metabolic medicine. By identifying estrogen-related receptors, particularly ERRα, as direct and potent regulators of mitochondrial biogenesis and activity, the research opens a crucial new avenue for drug development. The implications are far-reaching:
Targeted Therapies for Metabolic Disorders: The most immediate and profound impact lies in the potential to develop novel drugs for a wide spectrum of metabolic disorders. Conditions such as muscular dystrophy, characterized by progressive muscle degeneration and weakness, could benefit significantly from therapies that restore mitochondrial function and energy supply to muscle cells. Beyond rare genetic conditions, the widespread prevalence of metabolic dysfunction in aging populations, as well as in chronic diseases like cancer-related fatigue, multiple sclerosis, heart failure, and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, presents a vast patient population in urgent need of effective treatments. A drug that could activate ERRs would effectively act as an "exercise mimetic," offering the benefits of physical activity to those physically unable to engage in it.
Overcoming Current Therapeutic Limitations: The clear advantage of ERRα as a direct transcriptional regulator, capable of binding directly to DNA and activating gene expression, makes it a superior therapeutic target compared to indirect coactivators like PGC1α. This direct mechanism simplifies the challenge of drug design, increasing the likelihood of developing potent and specific small-molecule activators. This could accelerate the drug development pipeline, bringing much-needed treatments to patients more quickly.
Systemic Health Benefits Beyond Muscle: As Fan highlighted, the improvements in mitochondrial function instigated by ERR activation are unlikely to be confined solely to muscle tissue. Given the ubiquitous nature of mitochondria and their central role in all energy-demanding cells, enhancing their performance could confer systemic health benefits. This includes bolstering cardiovascular health by improving the energy supply to the heart muscle, enhancing cognitive function and protecting against neurodegeneration by optimizing brain cell metabolism, and potentially even improving immune responses and combating the fatigue often associated with chronic illnesses. The vision extends to a holistic improvement in vitality and resilience across multiple organ systems.
Future Research Directions: The Salk team’s work has not only provided answers but also opened new questions. Future research will undoubtedly delve deeper into the intricate functions and precise regulatory mechanisms of both the alpha- and gamma-type estrogen-related receptors. Understanding their specific roles, their interactions with other cellular pathways, and how their activity can be finely tuned will be critical for developing highly targeted and safe therapeutic agents. This may also lead to the identification of other synergistic targets or combination therapies that could further enhance mitochondrial health. The next steps will involve translating these promising preclinical findings into human trials, rigorously testing the efficacy and safety of ERR-targeting compounds, and ultimately moving towards clinical application.
This groundbreaking research, supported by significant funding from institutions including the National Institutes of Health, the Department of the Navy, the Larry L. Hillblom Foundation, the Wu Tsai Human Performance Alliance, the Henry L. Guenther Foundation, and the Waitt Foundation, represents a pivotal moment in our understanding of metabolic health. By illuminating the critical role of estrogen-related receptors, the Salk Institute has paved a clear path towards developing innovative therapies that could restore energy, alleviate fatigue, and dramatically improve the quality of life for millions living with metabolic dysfunction. The promise of an "exercise in a pill" may soon be a tangible reality.
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