LA JOLLA, CA – May 12, 2025 – In a landmark study poised to redefine our understanding and treatment of metabolic disorders, scientists at the Salk Institute have identified a critical role for estrogen-related receptors (ERRs) in orchestrating energy metabolism and combating muscle fatigue. Published today in the prestigious Proceedings of the National Academy of Sciences, the findings suggest that harnessing these previously underappreciated proteins could unlock powerful new therapeutic avenues for a wide spectrum of debilitating conditions, from muscular dystrophy to the metabolic decline associated with aging and chronic diseases.
The research pinpoints ERRs, particularly a specific subtype known as ERRα, as indispensable drivers of mitochondrial growth and activity within muscle cells. Mitochondria, often dubbed the "powerhouses" of the cell, are vital bean-shaped organelles responsible for converting the food we consume into adenosine triphosphate (ATP), the usable energy currency of life. When these cellular energy factories falter, the consequences can be profound, leading to severe muscle weakness, chronic fatigue, and widespread systemic dysfunction.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," explains senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, whose lab first discovered ERRs in 1988. "Our lab 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."
This discovery holds immense promise for the millions globally affected by mitochondrial dysfunction, a condition that can be congenital, affecting 1 in 5,000 individuals from birth, or acquired later in life due to aging or diseases such as cancer, multiple sclerosis (MS), heart disease, and dementia. The current scarcity of effective treatments for these conditions underscores the urgency and significance of the Salk team’s breakthrough.
The Unseen Battle: Understanding Mitochondrial Dysfunction
At the heart of nearly every physiological process, from thought to movement, lies the intricate dance of cellular metabolism. And at the epicenter of this dance are mitochondria. These microscopic organelles are far more than mere energy generators; they are complex signaling hubs involved in everything from calcium homeostasis to programmed cell death. Their proper functioning is paramount, especially in tissues with high energy demands, such as skeletal muscle, the heart, and the brain.
When mitochondria become dysfunctional, their ability to produce ATP plummets. This energy deficit can manifest in a myriad of ways, depending on which tissues are most affected. In muscles, it leads to the profound weakness and debilitating fatigue seen in muscular dystrophies and sarcopenia (age-related muscle loss). In the heart, it can contribute to heart failure. In the brain, cognitive decline and neurodegenerative diseases like Alzheimer’s and Parkinson’s have increasingly been linked to mitochondrial impairment. Even in cancer, altered mitochondrial metabolism is a hallmark, allowing cancer cells to fuel their aggressive growth.
The sheer prevalence of conditions touched by mitochondrial dysfunction makes it a global health challenge. The search for effective interventions has been long and arduous, often focusing on supportive therapies or symptomatic management rather than addressing the root cause. This latest research from the Salk Institute offers a paradigm shift, pointing towards a direct, molecular intervention that could restore the fundamental energy machinery of cells.
A Legacy of Discovery: Tracing the Salk Institute’s Path to ERRs
The journey to understanding estrogen-related receptors is deeply intertwined with the pioneering work conducted at the Salk Institute, a beacon of scientific innovation founded by Jonas Salk, the developer of the first safe and effective polio vaccine. The institution’s ethos of bold, curiosity-driven research has fostered environments where groundbreaking discoveries can flourish over decades.
Ronald Evans, a towering figure in molecular biology, has been at the forefront of this pursuit for over 40 years. His seminal work in the 1980s led to the landmark discovery of a family of proteins he named "nuclear hormone receptors." These extraordinary proteins act as molecular switches, responding to hormones and other signaling molecules by binding to specific DNA sequences and thereby controlling which genes are turned "on" or "off." This intricate gene regulatory mechanism underpins virtually every aspect of human physiology, from development and metabolism to reproduction and immunity.
Estrogen-related receptors (ERRs) emerged as a distinct branch within this vast family of nuclear hormone receptors. While they share structural similarities with classic estrogen receptors, their precise functions remained enigmatic for many years. However, their consistent presence in metabolically active tissues—like the heart and brain—hinted at a deeper role in energy regulation. This intriguing distribution fueled Evans’s team’s persistent inquiry, compelling them to explore ERRs’ potential in another high-energy organ: skeletal muscle.
This long-term commitment to fundamental research, often spanning decades, is characteristic of the Salk Institute and is precisely what allows for such profound breakthroughs. The initial discovery of ERRs in 1988 laid the groundwork for the meticulous investigations that have now culminated in their identification as indispensable drivers of mitochondrial health.
Unveiling the Mechanisms: ERRs as Regulators of Muscle Metabolism
Muscles are voracious consumers of energy, particularly during physical exertion. Exercise itself is one of the most potent natural signals for muscle cells to initiate mitochondrial biogenesis—the process by which cells increase the number and efficiency of their mitochondria to meet heightened energy demands. For individuals grappling with muscular and metabolic disorders, however, the very act of exercising can be excruciatingly difficult, if not impossible. This creates a cruel Catch-22: their muscles need more mitochondria, but they lack the capacity to induce their production through exercise. This dilemma spurred the Salk team to seek alternative, pharmacological pathways to stimulate mitochondrial biogenesis.
"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’s 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 systematically investigate the role of ERRs in muscle cell metabolism, Fan and his colleagues employed sophisticated genetic techniques. They selectively deleted three different forms of the receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – in the muscle tissues of mouse models and meticulously examined the resulting physiological and molecular changes.
Their initial observations revealed a complex interplay between the different ERR subtypes. While ERRα was found to be the most abundant receptor type in muscle, its individual deletion had surprisingly mild impacts under normal conditions. Intriguingly, the researchers discovered that ERRγ, despite making up only a small fraction (approximately 4%) of the total ERR population, possessed a remarkable compensatory capacity, stepping in to mitigate the effects of ERRα loss under baseline conditions. However, the true significance of ERRs became starkly evident when both ERRα and ERRγ were deleted simultaneously. This combined genetic knockout led to severe impairments in muscle mitochondrial activity, compromising their shape, size, and overall functional integrity.
This initial phase of the study provided crucial insights into the hierarchical and compensatory nature of ERRs in maintaining mitochondrial health. But the question remained: why such an apparent excess of ERRα? The team hypothesized that ERRα’s prominence might be tied to its role in the muscle’s adaptive response to physical stress, specifically exercise.
The Exercise Connection: ERRα as the Master Switch
To test their hypothesis, the Salk team introduced an exercise regimen for their mouse models, allowing them to run on mechanical wheels. This exercise reliably triggered mitochondrial biogenesis, providing a direct physiological context to assess ERRα’s involvement. The results were unequivocal: the loss of ERRα alone completely blocked exercise-induced mitochondrial biogenesis. This finding solidified ERRα’s position as a pivotal and indispensable player in the muscle’s adaptive response to physical activity, acting as a direct conduit between exertion and the cellular machinery responsible for energy production.
This discovery also illuminated a critical partnership. Previous research had identified PGC1α (Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha) as a "master regulator" of mitochondria throughout the body, known for its ability to promote mitochondrial biogenesis. However, PGC1α cannot directly bind to DNA and activate genes. Instead, it relies on partner proteins to execute its functions, making it a challenging target for direct therapeutic drug development.
The Salk team’s investigations revealed that after exercise, PGC1α was actively partnering with ERRα to drive mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the inherent ability to directly bind to the mitochondrial energetic genes and switch them "on." This direct transcriptional control makes ERRα an exceptionally attractive and accessible target for pharmacological intervention. By developing a drug that could specifically activate ERRα, scientists could potentially bypass the complexities of PGC1α’s indirect action and directly stimulate mitochondrial growth and function in muscle cells, mimicking the beneficial effects of exercise.
A Promising Therapeutic Horizon: Beyond Muscle Fatigue
The implications of the Salk Institute’s findings extend far beyond the immediate context of muscle fatigue and metabolic disorders. The fundamental role of ERRs in energy metabolism suggests that activating these receptors could yield broad, systemic benefits throughout the body.
"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 Weiwei Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
Consider the profound impact on patients suffering from diseases where mitochondrial dysfunction is a core component. For individuals with muscular dystrophy, a group of genetic diseases characterized by progressive muscle weakness and degeneration, an ERR-activating drug could potentially slow disease progression, improve muscle strength, and enhance quality of life. In the context of aging, where a decline in mitochondrial function contributes significantly to sarcopenia, frailty, and reduced vitality, such a therapeutic could represent a powerful anti-aging intervention, helping to maintain muscle mass and metabolic vigor.
Furthermore, the brain and heart, both organs with exceptionally high energy demands, are particularly vulnerable to mitochondrial compromise. Restoring robust mitochondrial function through ERR activation could offer neuroprotective benefits, potentially mitigating cognitive decline in Alzheimer’s disease or improving outcomes in conditions like multiple sclerosis. In cardiovascular disease, where impaired cardiac mitochondrial function is a common feature, targeting ERRs could represent a novel strategy to enhance heart muscle efficiency and resilience.
The discovery also opens new avenues for addressing metabolic syndrome, type 2 diabetes, and obesity, conditions where inefficient energy utilization and mitochondrial dysfunction play significant roles. By improving the cellular energy infrastructure, ERR activators could help cells process nutrients more efficiently, reduce metabolic stress, and potentially improve insulin sensitivity.
The Path Forward: From Bench to Bedside
The journey from a groundbreaking laboratory discovery to a widely available therapeutic is often long and complex, but the Salk team’s findings provide a clear and promising roadmap. The next critical steps will involve the development and testing of small-molecule drugs capable of selectively activating ERRα. This will require rigorous preclinical testing to assess efficacy, safety, and pharmacokinetics, followed by human clinical trials.
Future research will also continue to explore the nuanced functions and regulatory mechanisms of both alpha- and gamma-type receptors. While ERRα has emerged as the primary target for exercise-induced biogenesis, the compensatory role of ERRγ under normal conditions suggests that both subtypes may offer distinct therapeutic opportunities or could be targeted in combination for maximal effect. Understanding the precise molecular switches that control ERR activity will be crucial for developing highly specific and effective drugs with minimal side effects.
The collaborative nature of this research is evident in the extensive list of contributing authors, including Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes from Salk; Tae Gyu Oh from Salk and the University of Oklahoma; and Christopher Liddle from the University of Sydney, Australia. Such multidisciplinary efforts, bringing together expertise from various fields, are essential for tackling complex biological problems and translating fundamental discoveries into practical applications.
Funding the Future of Health
This transformative research was made possible through substantial support from a consortium of prestigious organizations and foundations. The National Institutes of Health (NIH) provided significant funding through multiple grants, including P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, and P30 AG068635. Additional crucial support came from the Department of the Navy (N00014-16-1-3159), underscoring the broad relevance of metabolic health to military readiness.
Further vital contributions were provided by 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. This diverse funding landscape highlights the recognition by both governmental agencies and private philanthropic organizations of the immense potential of this research to address some of the most pressing health challenges of our time. Such sustained investment in basic science is the bedrock upon which future medical breakthroughs are built.
In conclusion, the Salk Institute’s latest findings on estrogen-related receptors represent a monumental step forward in our quest to understand and combat metabolic dysfunction. By identifying ERRα as a central orchestrator of mitochondrial biogenesis and a highly druggable target, Ronald Evans and his team have opened a powerful new chapter in therapeutic development, offering a beacon of hope for millions living with debilitating muscle weakness and fatigue, and potentially paving the way for healthier, more energetic lives across the lifespan.
About the Author
