LA JOLLA, CA – May 12, 2025 – In a significant stride towards understanding and treating debilitating metabolic disorders, scientists at the Salk Institute have pinpointed a crucial family of proteins, known as estrogen-related receptors (ERRs), as a promising new target for repairing energy metabolism and combating muscle fatigue. This groundbreaking research, published today in the prestigious Proceedings of the National Academy of Sciences, illuminates a novel pathway to bolster cellular energy production, offering a beacon of hope for millions affected by conditions ranging from muscular dystrophy to the fatigue associated with aging and chronic diseases.
The study, led by veteran Salk professor Ronald Evans, reveals that these receptors play an indispensable role in governing the growth and activity of mitochondria – the microscopic powerhouses within our cells that convert food into usable energy. Particularly vital in muscle cells, which demand substantial fuel for movement, the findings suggest that developing drugs to enhance ERR activity could revolutionize treatment strategies for a wide array of conditions characterized by mitochondrial dysfunction.
The Ubiquitous Powerhouses: Mitochondria and Metabolic Dysfunction
Life itself is powered by energy, and at the cellular level, this energy is meticulously generated by tiny, bean-shaped organelles called mitochondria. These cellular power plants are responsible for respiration, converting the nutrients we consume into adenosine triphosphate (ATP), the primary energy currency of the cell. This process, known as cellular metabolism, is especially critical in tissues with high energy demands, such as skeletal muscle, the heart, and the brain, which continuously require substantial fuel to perform their functions.
However, this intricate system is vulnerable. Mitochondrial dysfunction, a condition where these vital organelles fail to produce energy efficiently, affects a significant portion of the global population. Roughly 1 in 5,000 individuals are born with primary mitochondrial diseases, genetic disorders that can lead to severe, multi-systemic issues from infancy. Beyond these congenital conditions, countless others develop metabolic dysfunction later in life. This acquired form is often a hallmark of aging, contributing to age-related decline in muscle strength (sarcopenia) and overall vitality. Moreover, it is intricately linked to a host of chronic and debilitating diseases, including various forms of cancer (contributing to cancer-related fatigue and cachexia), multiple sclerosis (MS) with its pervasive fatigue, heart disease (leading to heart failure), and neurodegenerative disorders like Alzheimer’s and other forms of dementia.
The consequences of mitochondrial dysfunction are profound and far-reaching. Impaired energy production can lead to a cascade of cellular problems, including oxidative stress, inflammation, and ultimately, cell death. For patients, this translates into profound muscle weakness, debilitating fatigue, cognitive impairment, and a general decline in organ function. Despite the widespread impact and severity of these conditions, effective treatments for mitochondrial dysfunction have remained elusive, often limited to supportive care or symptom management rather than addressing the root cause. This therapeutic gap underscores the urgent need for innovative approaches to restore cellular energy balance.
A Novel Therapeutic Avenue Emerges
The Salk Institute’s latest findings offer a compelling new direction for tackling this challenge. The research points to estrogen-related receptors (ERRs) as a key orchestrator of mitochondrial health. Unlike classic estrogen receptors, which respond to the hormone estrogen, ERRs are "orphan receptors" – meaning their natural activating ligands were unknown for many years, though synthetic activators and inhibitors have since been developed. Despite their structural resemblance to estrogen receptors, ERRs function independently of estrogen, primarily acting as constitutive transcriptional activators that regulate the expression of genes involved in energy metabolism.
The Salk scientists discovered that ERRs play a pivotal and previously underappreciated role in muscle cell metabolism. Their activity becomes particularly pronounced during periods of high energy demand, such as exercise. When muscles are challenged and require more fuel, ERRs act as crucial molecular switches, capable of both increasing the sheer number of mitochondria within muscle cells – a process known as mitochondrial biogenesis – and enhancing their overall energetic output. This dual action positions ERRs as master regulators, capable of fine-tuning the muscle’s energy infrastructure to meet physiological demands.
The implication of this discovery is immense: by developing a pharmacological agent that can selectively boost the activity of these estrogen-related receptors, scientists could potentially bypass the physical limitations faced by individuals with metabolic disorders. Such a drug could effectively "switch on" the mitochondrial machinery, restoring vital energy supplies and mitigating the debilitating muscle weakness and fatigue that characterize conditions like muscular dystrophy, chronic fatigue syndrome, and age-related muscle decline. This represents a paradigm shift, moving towards treatments that directly target the cellular energy crisis rather than merely managing its symptoms.
A Legacy of Discovery: Tracing the Origins of Nuclear Hormone Receptors
The recent breakthrough at the Salk Institute is not an isolated event but rather the culmination of decades of pioneering research spearheaded by Professor Ronald Evans, a titan in the field of molecular biology. His work has profoundly shaped our understanding of how hormones regulate gene expression and metabolism, laying the groundwork for countless therapeutic innovations.
Decades of Dedication: Professor Ronald Evans’ Pioneering Work
In the 1980s, a period of explosive growth in molecular biology, Ronald Evans led the landmark discovery of a novel family of proteins he aptly named "nuclear hormone receptors." This seminal work revolutionized biology, explaining how circulating hormones—from steroids like estrogen and testosterone to thyroid hormones and vitamin D—exert their profound effects on the body. These receptors, once activated by their specific hormone ligands, migrate to the nucleus of the cell where they bind directly to specific sequences of DNA, acting as transcription factors to precisely control which genes are turned "on" or "off." This intricate gene regulation underlies virtually every physiological process, from development and metabolism to reproduction and immunity.
The discovery of nuclear hormone receptors unveiled a fundamental mechanism of intercellular communication and gene control, opening up vast new avenues for understanding disease and developing targeted therapies. This class of proteins quickly became one of the most intensively studied families in pharmacology, with many successful drugs—from cancer treatments to anti-inflammatory medications—working by modulating the activity of specific nuclear hormone receptors.
From Orphan Receptors to Metabolic Masters
Estrogen-related receptors (ERRs) represent a fascinating branch of this extensive nuclear hormone receptor family. First identified by Evans’ lab in 1988, their structural similarity to classical estrogen receptors initially suggested they might also bind to estrogen. However, subsequent research revealed that ERRs do not respond to estrogen, leading to their classification as "orphan receptors" – receptors for which the natural activating ligand was unknown. Despite their enigmatic nature, Evans’ team was among the first to recognize their potential, observing early on their involvement in various aspects of energy metabolism.
Over the years, further studies revealed that ERRs are predominantly found in tissues with exceptionally high metabolic demands. Organs like the heart, the brain, the kidneys, and the liver, which require a constant and robust supply of ATP to function, show high levels of ERR expression. This consistent localization in energy-intensive tissues strongly hinted at their critical role in maintaining metabolic homeostasis. This observation naturally inspired Evans’ team to delve deeper into their potential function in another high-energy organ: skeletal muscle, a tissue whose metabolic activity dramatically fluctuates with physical exertion.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," states Professor Ronald Evans, senior author of the study and 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, after decades of dedicated research, 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." This long-term commitment to understanding these enigmatic receptors has now culminated in a finding with profound therapeutic implications.
Decoding the Muscle’s Energy Engine: Experimental Insights
To fully grasp the significance of the Salk team’s discovery, it is essential to understand the intricate experiments that unveiled the critical role of ERRs in muscle metabolism. The researchers employed sophisticated genetic models and rigorous physiological assessments to dissect the function of these receptors.
The Challenge of Exercise and the Quest for "Exercise Mimetics"
Skeletal muscles are highly adaptable tissues. When subjected to physical activity, they respond by increasing their capacity to generate energy. One of the most fundamental adaptive responses to exercise is mitochondrial biogenesis, a process wherein muscle cells increase both the number and the efficiency of their mitochondria. This cellular adaptation allows muscles to produce more ATP, enhancing endurance and reducing fatigue. In essence, exercise serves as a powerful natural signal for muscles to boost their energy factories.
However, for individuals grappling with muscular and metabolic disorders, or those weakened by aging or chronic illness, the very act of exercising can be incredibly difficult, if not impossible. A person suffering from muscular dystrophy, for instance, cannot engage in the strenuous activity required to trigger significant mitochondrial biogenesis. Similarly, patients with advanced heart failure or severe cancer-related fatigue are often physically incapable of sustained exercise. This limitation presents a significant therapeutic challenge: how can we stimulate the beneficial effects of exercise – particularly mitochondrial growth – in those who need it most but cannot perform it?
This unmet medical need has fueled a global scientific quest for "exercise mimetics" – pharmacological agents that can replicate the metabolic benefits of physical activity without the need for actual exertion. These drugs would be transformative, offering a way to improve muscle health, endurance, and overall metabolic function in vulnerable populations.
"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’ lab, articulating the core hypothesis behind their work. "This got us thinking – if we could understand precisely 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 foundational question drove the experimental design to uncover the molecular switches behind exercise adaptation.
Unraveling the Role of ERR Subtypes in Muscle Function
To systematically investigate the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues employed a powerful genetic approach using mouse models. They specifically deleted three different forms, or subtypes, of these receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – in the muscle tissues of the mice. This technique, known as conditional knockout, allowed them to selectively remove the genes encoding these receptors only in muscle cells, thereby minimizing potential confounding effects from other tissues. Following the genetic manipulation, the researchers meticulously examined the resulting effects on muscle mitochondrial activity, structure, and overall function.
Their initial observations yielded intriguing insights into the relative contributions of each ERR subtype:
- ERR Alpha (ERRα): They found that ERRα was the most abundant type of estrogen-related receptor in muscle tissue. Surprisingly, when only this single receptor was deleted, the impacts on muscle tissue were relatively mild under normal, resting conditions. This suggested a degree of redundancy or compensatory mechanisms at play.
- ERR Gamma (ERRγ): Despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, the gamma receptor (ERRγ) demonstrated a remarkable capacity to compensate for the loss of ERRα under baseline conditions. This highlights a complex interplay between the different subtypes, where less abundant forms can step up to maintain function when a more prevalent one is absent.
- Combined Deletion (ERRα and ERRγ): The true significance of ERRs became starkly evident when both the alpha and gamma types were simultaneously deleted from muscle cells. This combined loss led to severe impairments in mitochondrial function, manifest as significant reductions in mitochondrial activity, drastic alterations in their shape (often appearing fragmented or swollen), and a noticeable decrease in their overall size and density. This result strongly indicated that ERRα and ERRγ together are crucial for maintaining the structural integrity and functional prowess of muscle mitochondria.
The Indispensable Role of ERR Alpha in Exercise Adaptation
The observation that deleting ERRα alone had only mild impacts under normal conditions led the team to hypothesize that ERRα might play a more specialized role, particularly in situations of physiological stress or adaptation, such as exercise. They reasoned that the sheer abundance of ERRα might be a mechanism to enable muscles to adapt and grow in response to increased demands.
To test this hypothesis, the researchers introduced their genetically modified mice to mechanical running wheels. This controlled exercise regimen provided a consistent stimulus to trigger mitochondrial biogenesis in the muscles. By comparing the response of mice with intact ERRα to those lacking it, the team could assess ERRα’s specific involvement in exercise-induced adaptation.
The results were striking and definitive: the absence of ERRα alone completely blocked the exercise-induced mitochondrial biogenesis. Mice lacking ERRα in their muscles were unable to increase their mitochondrial numbers or improve their metabolic capacity in response to physical training, unlike their wild-type counterparts. This finding cemented ERRα’s role as an indispensable driver of the muscle’s adaptive response to exercise, revealing it as a central component of the body’s natural strategy for enhancing endurance and energy production.
PGC1alpha and ERR Alpha: A Powerful Partnership for Mitochondrial Biogenesis
The Salk team’s investigation didn’t stop at identifying ERRα’s critical role; they also delved into its molecular interactions. Previous research had established that exercise-induced mitochondrial growth was primarily 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, capable of coordinating the expression of numerous genes involved in mitochondrial function and biogenesis.
However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α is a co-activator; it cannot bind directly to DNA and thus cannot directly turn genes "on" or "off." Instead, it functions by partnering with other DNA-binding proteins (transcription factors) to exert its effects. This indirect mode of action makes PGC1α a more difficult target for small-molecule drugs, as it lacks a clear binding pocket that can be easily modulated. Developing drugs that effectively and specifically modulate co-activator function without disrupting a myriad of other protein-protein interactions has proven to be a complex pharmacological hurdle.
This is where the Salk team made another crucial discovery. When Evans’ lab meticulously examined muscle cells after exercise, they found compelling evidence that PGC1α was not acting alone. Instead, it was forming a powerful partnership with ERRα to drive the process of mitochondrial biogenesis. Crucially, and unlike PGC1α, ERRα possesses the ability to bind directly to specific DNA sequences within the promoters of mitochondrial energetic genes, effectively turning them "on." This direct binding capability positions ERRα as an ideal and highly "druggable" target for improving muscle’s mitochondrial performance. By activating ERRα, one could directly trigger the genetic programs necessary for enhanced mitochondrial function, offering a more direct and potentially more effective therapeutic strategy than attempting to modulate PGC1α.
Expert Perspectives: The Scientists Speak
The enthusiasm surrounding these findings is palpable among the researchers, who foresee a transformative impact on the landscape of metabolic medicine. Their statements underscore both the scientific significance of the discovery and its potential to alleviate human suffering.
A Paradigm Shift in Understanding Energy Metabolism
Professor Ronald Evans, whose foundational work on nuclear hormone receptors paved the way for this discovery, emphasizes the long journey of understanding ERRs and their pivotal role. "For decades, we’ve known that ERRs were involved in energy metabolism, but their precise mechanism and indispensable nature in muscle adaptation remained somewhat of a mystery," he reflects. "This study finally unveils ERRα as the central conductor of the muscle’s metabolic symphony, particularly during exercise. It’s not just another player; it’s the essential driver of mitochondrial growth and activity in our muscles. This revelation fundamentally shifts our understanding and provides a clear, actionable target for intervention."
Evans’ perspective highlights the deep scientific satisfaction that comes from solving a long-standing biological puzzle and immediately seeing its translational potential. The transition of ERRs from enigmatic "orphan receptors" to critical metabolic regulators represents a paradigm shift, focusing attention on a class of proteins whose therapeutic utility was previously overlooked.
Envisioning a Future with Enhanced Cellular Vitality
Weiwei Fan, the first author of the study, articulates the broader vision for these findings, extending beyond muscle tissue to encompass systemic health benefits. "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," says Fan. He elaborates on the interconnectedness of cellular energy and overall organ function: "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart, which are also highly dependent on robust energy production."
Fan’s comments paint a picture of a future where targeted ERR activation could lead to a holistic improvement in health. The brain, with its enormous energy requirements, and the heart, a tireless muscle, are particularly vulnerable to mitochondrial dysfunction. A therapy that can enhance mitochondrial vitality in these crucial organs could have profound implications for cognitive function, cardiovascular health, and overall longevity. This holistic perspective underscores the far-reaching potential of the Salk team’s work, positioning ERR activation as a strategy for enhancing not just muscle strength, but also systemic cellular vitality.
Far-Reaching Implications: A New Era for Metabolic Health
The Salk Institute’s discovery of estrogen-related receptors as critical regulators of mitochondrial health heralds a potentially new era for treating a wide array of diseases characterized by metabolic dysfunction. The implications are vast, promising improved quality of life for millions and opening new avenues for drug development.
Targeting a Spectrum of Debilitating Diseases
The direct and powerful link between ERRs and mitochondrial biogenesis makes them an exceptionally attractive therapeutic target for numerous conditions. Consider the following:
- Muscular Dystrophy: For patients suffering from progressive muscle degeneration, where muscle weakness and fatigue are debilitating, an ERR-activating drug could help preserve existing muscle mass and function by boosting energy production, potentially slowing disease progression and improving daily mobility.
- Aging-Related Sarcopenia: As people age, a natural decline in muscle mass and strength occurs, largely due to reduced mitochondrial function. An ERR modulator could act as an "exercise mimetic" for the elderly, helping to maintain muscle vitality, prevent falls, and preserve independence.
- Cancer-Related Fatigue and Cachexia: Many cancer patients experience profound fatigue and muscle wasting (cachexia) as side effects of their disease and treatments. Enhancing mitochondrial function via ERRs could combat this debilitating fatigue, improve physical resilience, and potentially enhance the efficacy of other cancer therapies.
- Multiple Sclerosis (MS) Fatigue: Fatigue is one of the most common and debilitating symptoms of MS, significantly impacting patients’ quality of life. If mitochondrial dysfunction plays a role in this fatigue, ERR activators could offer a novel approach to restore energy levels and reduce symptom burden.
- Heart Failure: The heart is a metabolic powerhouse, constantly pumping blood. In heart failure, the heart muscle becomes weakened, often due to impaired mitochondrial function. Drugs that boost ERRs could potentially improve the heart’s energy efficiency, enhancing its contractile function and overall health.
- Neurodegenerative Diseases (e.g., Alzheimer’s, Parkinson’s): While the primary focus of this study was muscle, the high ERR expression in the brain suggests potential benefits for neurological disorders. Mitochondrial dysfunction is a known contributor to neurodegeneration. Improving neuronal energy metabolism could protect brain cells, slow disease progression, and improve cognitive function in conditions like Alzheimer’s and Parkinson’s.
The ability of ERRs to directly bind to DNA and activate genes involved in mitochondrial energy production offers a more direct and potentially more effective pharmacological strategy compared to targeting indirect co-activators. This "druggability" is a critical factor for successful translation from laboratory discovery to clinical application.
Beyond Muscle: Systemic Benefits for Brain and Heart
The vision of the Salk researchers extends beyond mere muscle enhancement. As Fan highlights, the potential for "whole-body benefits" is a particularly exciting aspect of this discovery. The brain, consuming a disproportionate amount of the body’s energy, and the constantly working heart, are exquisitely sensitive to changes in mitochondrial health. By improving energy metabolism across these vital organ systems, ERR-targeting therapies could offer multifaceted health advantages.
Imagine a single therapeutic approach that not only strengthens weakened muscles but also bolsters cognitive function, enhances cardiovascular resilience, and combats systemic fatigue. Such a drug could represent a truly transformative intervention, improving the quality of life for patients suffering from complex, multi-systemic disorders where energy deficits are a common underlying thread. The development of such therapies could also significantly reduce the economic burden associated with chronic diseases by preventing or mitigating their most debilitating symptoms.
The Path Forward: Refining Our Understanding and Developing Therapies
Understanding how estrogen-related receptors function in muscle cells creates new opportunities to treat all parts of the body affected by mitochondrial dysfunction. However, this is just the beginning. Future research will continue to explore the nuanced function and regulation of both alpha- and gamma-type receptors. While ERRα appears to be the primary driver of exercise-induced biogenesis, the compensatory role of ERRγ under normal conditions suggests it also holds significant therapeutic promise and might be targeted for specific clinical applications.
Researchers will need to delve deeper into the precise molecular mechanisms by which PGC1α and ERRα interact, identifying potential protein-protein interaction sites that could also be targeted. Furthermore, the development of highly selective ERR agonists – drugs that specifically activate these receptors without undesirable off-target effects – will be paramount. This involves extensive preclinical testing to ensure efficacy, safety, and optimal dosing. Clinical trials will then be necessary to validate these findings in human patients, moving from mouse models to tangible improvements in human health.
The Salk Institute’s latest discovery offers a profound sense of optimism. By identifying estrogen-related receptors as indispensable drivers of cellular energy production, particularly in muscle, the team has illuminated a clear and promising path toward developing novel therapies. This research moves us closer to a future where the debilitating effects of metabolic dysfunction can be effectively reversed, empowering individuals to regain strength, vitality, and a higher quality of life.
Authors and Funding:
Other authors involved in this groundbreaking 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.
The work was generously supported by 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.
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