LA JOLLA, CA – May 12, 2025 – In a landmark discovery poised to redefine therapeutic strategies for a spectrum of debilitating metabolic disorders, scientists at the Salk Institute have identified a crucial role for a group of proteins known as estrogen-related receptors (ERRs). A new study, published today in the Proceedings of the National Academy of Sciences, reveals that these receptors are indispensable drivers of mitochondrial growth and activity in muscle cells, offering a promising new target for repairing energy metabolism and alleviating muscle fatigue across various conditions, from aging-related decline to severe genetic diseases.
The research illuminates a fundamental mechanism by which our bodies generate energy, particularly under stress, and points to a potent pharmacological avenue for patients who currently face limited treatment options. The findings suggest that by developing drugs to boost the activity of these overlooked receptors, scientists could restore vital energy supplies to countless individuals grappling with chronic fatigue and muscle weakness.
A New Frontier in Metabolic Health: Targeting Estrogen-Related Receptors
H2: Main Facts: Unlocking Cellular Energy with ERRs
At the heart of every cell, tiny, bean-shaped powerhouses called mitochondria tirelessly convert the food we eat into adenosine triphosphate (ATP), the usable energy currency that fuels all biological processes. This intricate cellular-level metabolism is critically important in muscle cells, which demand substantial energy to power everything from a subtle twitch to vigorous exercise. However, for a significant portion of the global population, this vital energy production system falters. An estimated 1 in 5,000 individuals are born with inherent mitochondrial dysfunction, while countless others develop metabolic impairments later in life, often linked to the natural process of aging or the onset of severe diseases such as cancer, multiple sclerosis (MS), heart disease, and neurodegenerative conditions like dementia.
The consequences of mitochondrial dysfunction are far-reaching, manifesting as chronic fatigue, muscle weakness, organ failure, and a reduced quality of life. Despite the pervasive impact, effective treatments for these complex metabolic disorders remain elusive, often focusing on managing symptoms rather than addressing the root cause.
It is against this backdrop of urgent unmet medical need that the Salk Institute’s recent findings emerge as a beacon of hope. The study pinpoints a group of proteins—estrogen-related receptors—as a potentially powerful and previously underestimated therapeutic target. Salk scientists have uncovered that ERRs play a pivotal and indispensable role in orchestrating muscle cell metabolism, particularly when energy demands surge, such as during physical exertion. These receptors possess the remarkable ability to increase both the sheer number of mitochondria within muscle cells and enhance their energetic output, thereby bolstering the body’s energy reserves.
Published in the esteemed Proceedings of the National Academy of Sciences on May 12, 2025, the research indicates a clear path forward: designing pharmaceutical agents capable of activating or augmenting the function of estrogen-related receptors could represent a transformative approach to restoring energy supplies in individuals plagued by metabolic disorders, including devastating conditions like muscular dystrophy. This breakthrough promises not only to alleviate symptoms but to fundamentally address the cellular energy deficit that underpins these debilitating diseases.
H2: Chronology: From Foundational Discovery to Targeted Therapy
The journey to understanding estrogen-related receptors and their profound impact on energy metabolism is deeply rooted in decades of pioneering research at the Salk Institute, particularly the groundbreaking work of senior author Ronald Evans.
H3: The Genesis of Nuclear Hormone Receptors
The story begins in the 1980s, a pivotal era in molecular biology when Evans led the landmark discovery of a vast family of proteins he aptly named "nuclear hormone receptors." These extraordinary receptors function as molecular switches, residing within the cell’s nucleus and acting as sophisticated conduits between hormonal signals and genetic expression. Activated by specific hormones or other signaling molecules, these receptors attach directly to our DNA, meticulously controlling which genes are turned "on" or "off." This fundamental mechanism dictates a vast array of biological processes, from development and reproduction to metabolism and immune response. Evans’ initial discovery of this family revolutionized endocrinology and our understanding of gene regulation.
H3: Unveiling Estrogen-Related Receptors (ERRs)
Estrogen-related receptors represent a distinct and intriguing branch of this expansive nuclear hormone receptor family. Evans’ lab first identified these receptors in 1988, noting their structural resemblance to classic estrogen receptors, yet their functional role remained largely enigmatic at the time. Unlike their well-understood estrogenic counterparts, ERRs were initially considered "orphan receptors" because no endogenous ligand (a molecule that naturally binds to and activates the receptor) was immediately apparent. However, Evans’ team was among the first to presciently recognize their potential involvement in energy metabolism, a hypothesis that has steadily gained traction over the years.
ERRs are frequently found in tissues and organs characterized by high energy demands, such as the heart and the brain – organs that, much like muscles, rely heavily on robust mitochondrial function to sustain their continuous activity. This intrinsic association with energy-intensive tissues naturally inspired Evans’ team to delve deeper into their potential role in regulating metabolism within another high-energy organ: skeletal muscle.
H3: The Current Study: A Deep Dive into Muscle Metabolism
The present study represents the culmination of this long-standing inquiry, focusing specifically on the intricate interplay between ERRs and muscle energetics. The researchers hypothesized that if ERRs were indeed critical for energy metabolism, their role would be particularly evident in skeletal muscle, especially under conditions of increased energy demand like exercise. This directed the Salk team to embark on the detailed experimental work that has now unveiled ERRs as "indispensable drivers" of mitochondrial activity. The meticulous research, spanning several years of dedicated effort, culminated in its publication on May 12, 2025, solidifying its place as a significant advancement in the field of metabolic research.
H2: Supporting Data: The Intricate Dance of Mitochondria and ERRs
The human body’s capacity for movement, thought, and even basic cellular maintenance is inextricably linked to the efficiency of its mitochondria. These microscopic organelles are far more than simple power plants; they are dynamic, responsive structures that adapt their number, size, and activity based on the cell’s energy needs. In skeletal muscles, this adaptability is paramount. Muscles are prodigious consumers of energy, particularly during physical activity. Indeed, exercise itself is one of the most potent natural signals for triggering mitochondrial biogenesis—the intricate cellular process by which a cell increases the number of its mitochondria to generate more fuel.
H3: The Challenge of Metabolic Dysfunction
However, for individuals afflicted with muscular and metabolic disorders, the very act of exercising can be incredibly challenging, if not impossible. This creates a cruel paradox: their muscles desperately need more mitochondria, but they lack the physical capacity to induce the biogenesis process through natural means. This fundamental limitation has spurred scientists to search for alternative, pharmacological ways to stimulate mitochondrial growth and function.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains first author Weiwei Fan, a staff scientist in Evans’ laboratory. "This got us thinking—if we could understand precisely how exercise induces mitochondrial biogenesis, we might be able to target those same underlying mechanisms pharmacologically. This would allow us to trigger this vital process in people who are simply too weak to exercise, offering them a chance to restore their energy levels and improve muscle function."
H3: Experimental Design and Key Discoveries
To rigorously test their hypothesis regarding the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues meticulously designed a series of experiments using genetically modified mouse models. They systematically deleted three distinct forms of ERRs—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of these mice and then carefully examined the resulting physiological and cellular effects.
Their initial observations revealed that ERRα was the most abundant type of receptor found in muscle tissue, suggesting a prominent role. Intriguingly, however, the loss of this single receptor type alone resulted in only mild, albeit noticeable, impacts on muscle tissue function under normal, resting conditions. This led the researchers to investigate compensatory mechanisms.
They discovered that ERRγ, despite constituting a mere 4% of the total estrogen-related receptors in muscle, possessed a remarkable capacity to compensate for the absence of ERRα under typical physiological circumstances. This suggested a degree of redundancy or functional overlap among the ERR subtypes. However, the true criticality of these receptors became starkly apparent when both the alpha and gamma types were simultaneously deleted. This combined deletion led to severe and profound impairments in muscle mitochondrial activity, significantly altering their shape, size, and overall functional integrity. The muscles of these mice were severely compromised in their energy-generating capacity.
H3: Unmasking ERRα’s Indispensable Role in Exercise Adaptation
The initial findings prompted a deeper question: if ERRα is the most abundant type, why did its singular deletion have only mild impacts under normal conditions? The team hypothesized that ERRα’s critical function might become evident when muscles are pushed to their limits, specifically during exercise, which demands significant metabolic adaptation and growth. To test this, the researchers had their genetically modified mice engage in exercise on mechanical wheels. This controlled exercise regimen predictably triggered mitochondrial biogenesis in wild-type mice, providing an ideal experimental setup to assess ERRα’s involvement.
The results were unequivocal: losing ERRα alone completely blocked the exercise-induced mitochondrial biogenesis. This pivotal experiment definitively demonstrated that ERRα is not just present but is an indispensable mediator of the muscle’s adaptive response to physical activity, acting as a crucial switch for increasing mitochondrial number and capacity when energy demands are high.
H3: The PGC1α Connection: Why ERRs are a Superior Therapeutic Target
Previous scientific studies had established 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, orchestrating many aspects of their biogenesis and function. However, a significant challenge with PGC1α as a therapeutic target lies in its mode of action. 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 relies on partnering with other proteins—transcription factors—to exert its genetic control. This indirect mechanism makes PGC1α a more complex and consequently more difficult target for the development of direct-acting therapeutic drugs.
The Salk lab’s subsequent investigation into muscle cells following exercise provided the crucial missing piece of the puzzle. They discovered that PGC1α was indeed partnering with ERRα to drive mitochondrial biogenesis. But critically, unlike PGC1α, ERRα possesses the unique ability to bind directly to mitochondrial energetic genes and activate them. This direct transcriptional control mechanism positions ERRα as a far more accessible and promising target for pharmacological intervention aimed at improving muscle’s mitochondrial performance. By directly engaging ERRα, researchers could potentially bypass the complexities of indirect coactivator systems and achieve a more precise and potent therapeutic effect.
H2: Official Responses: Vision for a Healthier Future
The Salk Institute scientists behind this groundbreaking work articulate a clear vision for how their findings could revolutionize the treatment of metabolic disorders and improve overall health. Their statements underscore both the scientific rigor of the study and the profound clinical implications.
Senior author Ronald Evans, a distinguished professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, emphasized the historical context and the current significance of the discovery. "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," Evans stated, highlighting the long road from initial identification to functional elucidation. "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."
Evans’ use of the word "indispensable" carries significant weight, signaling that ERRs are not merely contributors but essential orchestrators of muscle energy metabolism. His perspective, forged over decades of pioneering research into nuclear hormone receptors, lends considerable authority to the assertion that ERRs represent a highly viable and impactful therapeutic target. The potential to address muscle weakness and fatigue, common and debilitating symptoms across a wide array of conditions, speaks to the broad applicability of this research.
First author Weiwei Fan, whose meticulous experimental work was central to these findings, elaborated on the broader systemic benefits that could arise from 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 explained. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
Fan’s optimistic outlook points to the systemic nature of mitochondrial dysfunction. Since mitochondria are fundamental to the energy production of virtually all cells, enhancing their function through ERR activation could yield widespread health improvements. This holistic perspective suggests that a treatment initially developed for muscle fatigue could cascade into unexpected but highly beneficial effects on cognitive function, cardiovascular health, and potentially even the resilience of other vital organs. The vision is not just about stronger muscles, but a healthier, more energized individual from head to toe.
H2: Implications: Paving the Way for Transformative Therapies
The elucidation of how estrogen-related receptors function as direct regulators of mitochondrial biogenesis and energetic output in muscle cells opens up entirely new and exciting avenues for therapeutic development. This research offers a tangible path towards addressing a constellation of diseases characterized by compromised energy metabolism, promising to transform the lives of millions.
H3: A New Class of Drugs for Metabolic Disorders
The most immediate and profound implication of this study is the potential to develop a novel class of pharmacological agents specifically designed to activate or modulate estrogen-related receptors. Such drugs could effectively mimic the beneficial effects of exercise at a molecular level, stimulating mitochondrial growth and enhancing energy production in individuals who are physically unable to exercise due to severe muscle weakness, chronic fatigue, or other debilitating conditions. This holds particular promise for patients suffering from inherited metabolic disorders such as muscular dystrophy, where muscle wasting and weakness are progressive and relentless, or for those battling the pervasive fatigue associated with conditions like multiple sclerosis, cancer, or age-related sarcopenia. By bypassing the need for physical exertion, these drugs could provide a lifeline, restoring muscle vitality and functional independence.
H3: Broader Health Benefits Across Organ Systems
Beyond skeletal muscle, the implications extend to other high-energy-demanding organs that are frequently affected by mitochondrial dysfunction. As Weiwei Fan articulated, improving mitochondrial function and energy metabolism through ERR activation could have profound beneficial effects on the brain and heart. Neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as various forms of dementia, are increasingly linked to impaired mitochondrial function in neurons. Similarly, heart failure and other cardiovascular diseases often involve a significant component of energetic compromise in cardiac muscle cells. A therapeutic strategy targeting ERRs could therefore offer a versatile approach to bolstering the energetic resilience of these critical organ systems, potentially preventing disease progression or even reversing some aspects of cellular damage.
H3: Advancing the Understanding of Aging and Chronic Disease
The study also provides critical insights into the fundamental processes underlying aging. As we age, mitochondrial function naturally declines, contributing to reduced energy levels, decreased muscle mass and strength (sarcopenia), and increased susceptibility to chronic diseases. By identifying ERRs as key regulators of mitochondrial health, this research offers a molecular handle on some of the core mechanisms of aging. Future therapies based on ERR activation could potentially slow down age-related metabolic decline, extending healthspan and improving the quality of life for an aging global population.
H3: Future Research and Collaboration
The Salk team’s work is not an endpoint but a significant milestone. Future research will undoubtedly continue to explore the nuanced functions and regulatory mechanisms of both the alpha- and gamma-type estrogen-related receptors. Understanding their precise interplay, specific activators, and downstream signaling pathways will be crucial for developing highly targeted and effective therapeutic interventions. This will likely involve detailed structural studies, high-throughput drug screening, and further preclinical and ultimately clinical trials to translate these promising laboratory findings into approved medications. The multidisciplinary nature of this research, as evidenced by the diverse list of authors and funding sources, underscores the collaborative spirit essential for tackling such complex biological challenges.
In conclusion, the Salk Institute’s discovery of estrogen-related receptors as indispensable drivers of mitochondrial health represents a powerful leap forward in our understanding of metabolism and a beacon of hope for individuals suffering from debilitating energy deficits. This research not only illuminates a fundamental biological process but also lays the groundwork for transformative therapies that could revolutionize the treatment of metabolic disorders, improve muscle function, and enhance overall health across the lifespan. The future of metabolic medicine, fueled by the power of ERR activation, appears brighter than ever.
Other authors on this 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.
This work was generously supported by: the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), Department of the Navy (N00014-16-1-3159), Larry L. Hillblom Foundation, Inc. (2021-D-001-NET), Wu Tsai Human Performance Alliance, Henry L. Guenther Foundation, and Waitt Foundation.
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