LA JOLLA, CA – May 12, 2025 – In a discovery poised to revolutionize the treatment of metabolic disorders and chronic fatigue, scientists at the Salk Institute have identified a crucial role for a group of proteins known as estrogen-related receptors (ERRs) in repairing energy metabolism and alleviating muscle fatigue. This groundbreaking research suggests that targeting these receptors could unlock a powerful new therapeutic strategy for a range of debilitating conditions, from muscular dystrophy to the metabolic dysfunctions associated with aging and diseases like cancer, multiple sclerosis (MS), heart disease, and dementia.
The findings, published today in the prestigious Proceedings of the National Academy of Sciences, illuminate how ERRs, particularly the alpha subtype, act as indispensable drivers of mitochondrial growth and activity within muscle cells. Mitochondria, often dubbed the "powerhouses of the cell," are essential for converting the food we consume into usable energy. When these microscopic structures falter, the body’s ability to fuel itself is compromised, leading to profound weakness and fatigue.
"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 laboratory pioneered the discovery of ERRs decades ago. "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 study offers a beacon of hope for the one in 5,000 people born with dysfunctional mitochondria, as well as the millions who acquire metabolic dysfunction later in life, for whom effective treatments remain elusive. By understanding how ERRs orchestrate the production and efficiency of mitochondria, scientists envision a future where drugs could mimic the energizing effects of exercise, even in those too weak to perform it.
The Silent Epidemic of Mitochondrial Dysfunction
Across the vast landscape of human physiology, the delicate balance of energy production is paramount. At the cellular level, this intricate process is orchestrated by mitochondria. These tiny, bean-shaped organelles reside within nearly every cell, tirelessly transforming nutrients into adenosine triphosphate (ATP), the primary energy currency of the body. Their role is particularly critical in high-demand tissues like muscle cells, which require a continuous and abundant supply of fuel to power movement, contraction, and recovery.
However, this vital machinery is surprisingly vulnerable. Mitochondrial dysfunction, a condition where these cellular powerhouses fail to operate efficiently, affects a significant portion of the global population. While a substantial number of individuals are born with inherited mitochondrial diseases, manifesting in severe and often progressive symptoms from birth or early childhood, many others develop metabolic dysfunction over their lifespan. This acquired form is increasingly recognized as a hallmark of aging and a common thread in the pathology of numerous chronic diseases, including various cancers, neurodegenerative conditions like multiple sclerosis (MS) and dementia, and cardiovascular ailments such as heart disease.
The consequences of mitochondrial dysfunction are far-reaching and debilitating. Patients often experience profound muscle weakness, persistent fatigue, exercise intolerance, and a general decline in physical and cognitive function. This pervasive energy deficit impacts nearly every organ system, compromising quality of life and accelerating disease progression. The challenge for clinicians and researchers has been the scarcity of effective treatments. Current approaches often focus on symptom management or supportive care, rather than addressing the root cause of the energy deficit. This therapeutic gap underscores the urgent need for novel interventions that can restore mitochondrial health and cellular metabolic vigor.
A Legacy of Discovery: Unearthing Nuclear Hormone Receptors
The recent breakthrough at the Salk Institute is not an isolated event but rather the culmination of decades of pioneering research, particularly the foundational work spearheaded by Professor Ronald Evans. In the 1980s, Evans led the landmark discovery of a vast family of proteins he aptly named "nuclear hormone receptors." This seminal work fundamentally reshaped our understanding of how cells respond to hormones and regulate gene expression.
Nuclear hormone receptors are a unique class of proteins that reside within the cell’s nucleus, acting as molecular switches. When activated by specific hormones or other signaling molecules, these receptors bind directly to our DNA, specifically to regulatory regions of genes. This binding event dictates whether a particular gene gets "turned on" (expressed) or "turned off" (silenced), thereby controlling a myriad of cellular processes, from development and metabolism to inflammation and reproduction. This intricate system of gene regulation is central to virtually every aspect of biological function.
Among the many branches of this expansive family, Evans’ lab also identified the estrogen-related receptors (ERRs). Initially, their precise function remained somewhat enigmatic, as they resembled classic estrogen receptors but did not bind to estrogen. However, early investigations by Evans’ team hinted at their critical involvement in energy metabolism, noting their prevalence in tissues with high energy demands, such as the heart and brain. These initial observations laid the groundwork for the current study, inspiring researchers to delve deeper into the potential role of ERRs in regulating metabolism within another high-energy organ: skeletal muscle. The historical context of this research underscores the iterative nature of scientific discovery, where initial insights often serve as springboards for future, more profound revelations.
The Genesis of the Current Study: Targeting Metabolic Pathways
The inherent energy demands of skeletal muscle, particularly during physical activity, naturally drew the attention of Evans’ team to the potential significance of ERRs in this tissue. Muscles are metabolic powerhouses, constantly adapting their energy production to meet varying demands. When we engage in exercise, our muscles signal for an increase in energy-producing capacity through a remarkable biological process called mitochondrial biogenesis. During biogenesis, cells actively increase both the number and the size of their mitochondria, effectively expanding their cellular energy factories to produce more fuel. This adaptive response is a cornerstone of physical fitness and endurance.
However, the very act of exercise, which naturally stimulates this vital process, poses a significant barrier for individuals suffering from muscular and metabolic disorders. For patients with conditions like muscular dystrophy, chronic fatigue syndrome, or age-related sarcopenia, the physical exertion required to trigger mitochondrial biogenesis is often impossible or severely limited. This creates a vicious cycle: weakened muscles need more energy, but the means to generate that energy (exercise) is out of reach.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," says first author Weiwei Fan, a staff scientist in Evans’ lab, articulating the core hypothesis that guided their investigation. "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 fundamental question ignited the detailed experimental program, aiming to uncover the molecular levers that drive mitochondrial biogenesis, with the ultimate goal of translating this knowledge into therapeutic interventions for those most in need.
Pioneering Experiments: Unveiling ERR’s Role
To definitively ascertain the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues embarked on a meticulously designed series of experiments utilizing sophisticated genetic models. Their primary strategy involved generating mice with specific deletions of the ERR genes within their muscle tissues. There are three known forms of these receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ). By selectively removing one or more of these forms, the researchers could observe the resulting physiological and metabolic consequences, thereby inferring the specific functions of each receptor subtype.
Initial investigations revealed that ERRα was the most abundant subtype within muscle tissue. However, surprisingly, the loss of ERRα alone had only mild impacts on muscle mitochondrial activity under normal, sedentary conditions. This led the team to investigate potential compensatory mechanisms. They discovered that the gamma receptor (ERRγ), despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, possessed a remarkable capacity to compensate for the absence of ERRα, maintaining mitochondrial function. This redundancy suggested a robust system for preserving energy homeostasis.
The critical insight emerged when both the alpha and gamma types of ERRs were deleted simultaneously. This dual deletion resulted in serious impairments in muscle mitochondrial activity, profoundly affecting their shape and size. These muscles exhibited a clear and significant energy deficit, underscoring the collective importance of ERRs in maintaining mitochondrial health.
The question then arose: if ERRγ could compensate for ERRα under normal conditions, why was there such an overwhelming abundance of the alpha-type receptor (ERRα) in muscle? The scientists hypothesized that ERRα’s prominence might be tied to its role in the muscle’s adaptive response to increased energy demands, particularly during exercise. To test this hypothesis, the team introduced a crucial component to their experimental design: voluntary exercise. They allowed their genetically modified mice to exercise on mechanical wheels, a well-established method to induce mitochondrial biogenesis in healthy muscles.
This exercise experiment proved to be pivotal. It unequivocally demonstrated that losing ERRα alone could entirely block the exercise-induced mitochondrial biogenesis. Even with the presence of ERRβ and ERRγ, the absence of ERRα rendered the muscles incapable of increasing their mitochondrial content in response to physical exertion. This finding highlighted ERRα not just as a component of mitochondrial regulation, but as an indispensable, non-redundant driver of the muscle’s adaptive energy response to exercise. The meticulously controlled deletions and the inclusion of an exercise challenge provided compelling evidence for ERRα’s unique and critical role.
The Intricacies of Mitochondrial Biogenesis: ERRα as a Direct Path to Therapeutic Intervention
For years, the scientific community has recognized another protein, PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as the "master regulator" of mitochondria throughout the body. PGC1α plays a central role in orchestrating mitochondrial biogenesis and adaptive thermogenesis, making it a highly attractive, albeit challenging, target for therapeutic development. The inherent difficulty with PGC1α, however, lies in its nature as a coactivator. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to DNA to turn genes on or off. Instead, it operates indirectly, requiring partner proteins to execute its regulatory functions on specific genes. This indirect mode of action makes PGC1α a more complex and thus more difficult target for the precise development of therapeutic drugs, as any intervention would need to account for its interaction with multiple, varied partners.
The Salk Institute’s latest research beautifully clarifies this complex regulatory landscape, positioning ERRα as a more direct and therefore potentially more tractable therapeutic target. When Evans’ lab meticulously examined muscle cells after exercise, they uncovered a crucial partnership: PGC1α was indeed activated, but it was working in concert with ERRα to drive the process of mitochondrial biogenesis. This collaborative effort revealed the functional bridge between the master regulator and the direct gene-binding capabilities of ERRs.
What makes ERRα particularly compelling as a drug target is its ability to directly bind to the regulatory regions of mitochondrial energetic genes and activate their expression. Unlike PGC1α, which relies on intermediaries, ERRα possesses the intrinsic molecular machinery to directly switch these vital genes "on," thereby initiating and enhancing mitochondrial performance. This direct action provides a clearer and potentially more efficient pathway for pharmaceutical intervention. Developing a drug that specifically activates ERRα could offer a streamlined approach to boosting mitochondrial function, circumventing the complexities associated with indirect coactivators like PGC1α. This distinction is critical in drug discovery, where the specificity and directness of a target often correlate with greater therapeutic efficacy and fewer off-target effects. The identification of ERRα as a direct transcriptional activator significantly elevates its promise for improving muscle’s mitochondrial performance and overall metabolic health.
Paving the Way for Novel Therapies
The comprehensive understanding of how estrogen-related receptors function in muscle cells, and particularly the indispensable role of ERRα, opens an exciting new frontier in medical science. The implications of this discovery are profound, offering a tangible path toward developing novel therapeutic strategies for a wide array of conditions characterized by mitochondrial dysfunction and metabolic imbalance. The immediate and most promising application lies in the treatment of metabolic disorders such as muscular dystrophy, where muscle weakness and fatigue are central to the disease’s devastating progression. By developing drugs that can specifically activate or enhance the activity of ERRs, particularly ERRα, scientists envision a future where patients could experience restored energy supplies within their muscle cells, leading to improved strength, endurance, and overall quality of life.
The potential for such targeted pharmacological intervention is particularly significant for individuals who are too weak or ill to engage in physical exercise, which is currently the most potent natural stimulus for mitochondrial biogenesis. A drug that could mimic the beneficial effects of exercise at a cellular level would offer an unprecedented opportunity to improve the health and functional capacity of millions.
"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," emphasizes Weiwei Fan, highlighting the broader systemic implications of their research. The intricate network of mitochondrial function extends far beyond muscle tissue. Improving mitochondrial function and energy metabolism is a fundamental biological imperative that could yield widespread benefits across multiple organ systems.
Beyond Muscles: Systemic Health Benefits
The vision extends beyond merely strengthening muscles. Enhanced mitochondrial function could bolster the resilience and performance of other high-energy organs, including the brain and the heart. In the brain, robust mitochondrial activity is essential for cognitive function, memory, and protection against neurodegenerative diseases. In the heart, a tireless organ demanding immense energy, improved mitochondrial efficiency could be crucial for preventing and treating conditions like heart failure.
This holistic perspective on ERR activation suggests a future where therapies might not only alleviate muscle fatigue but also contribute to improved cardiovascular health, enhanced cognitive vitality, and even potentially slow aspects of age-related decline. For diseases like cancer, where metabolic reprogramming is a hallmark, or multiple sclerosis, which often presents with profound fatigue, a deeper understanding of ERR pathways could offer innovative avenues for intervention. The interconnectedness of metabolic health means that a breakthrough in one area, such as muscle energy, often cascades into benefits for the entire physiological system.
The Road Ahead: From Bench to Bedside
While the findings are incredibly promising, the journey from laboratory discovery to clinical application is a complex and arduous one. Future research will undoubtedly focus on several critical areas. A deeper exploration into the nuanced functions and regulatory mechanisms of both alpha- and gamma-type receptors will be essential. Understanding how these subtypes interact, their specific ligands (if any beyond PGC1alpha), and their precise roles in different physiological contexts could unveil additional therapeutic targets and refine drug development strategies.
The next crucial step involves the development and rigorous testing of small-molecule compounds that can selectively activate ERRs. This process will require extensive screening, optimization, and preclinical studies to assess efficacy, safety, and potential side effects. Identifying compounds that can precisely modulate ERR activity without causing unintended consequences will be paramount. Following successful preclinical validation, human clinical trials will be necessary to confirm the safety and therapeutic potential of ERR-targeting drugs in patients suffering from various metabolic and muscular disorders.
The Salk Institute’s latest discovery, supported by a consortium of funding bodies 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 significant stride forward in our quest to conquer debilitating energy-related ailments. The collaborative spirit of the research, involving scientists from Salk, the University of Oklahoma, and the University of Sydney, Australia, underscores the global effort behind such transformative scientific endeavors.
This research offers a powerful new lens through which to view and address metabolic dysfunction. By illuminating the critical role of estrogen-related receptors, particularly ERRα, in orchestrating our cellular energy factories, the Salk Institute has not only deepened our fundamental biological understanding but also ignited a tangible hope for millions. The prospect of restoring vitality and mitigating fatigue through targeted ERR activation heralds a new era in metabolic medicine, promising a healthier, more energetic future for those currently battling the profound challenges of energy deficiency.
Other authors involved in 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.
About the Author
