LA JOLLA, CA – May 12, 2025 – A groundbreaking study from the Salk Institute has revealed that a previously underappreciated class of proteins, known as estrogen-related receptors (ERRs), could hold the key to repairing impaired energy metabolism and alleviating muscle fatigue. This pivotal discovery offers a potent new therapeutic target for a myriad of debilitating conditions ranging from muscular dystrophy to age-related decline, promising a new era in the fight against widespread metabolic disorders.
Published today in the esteemed journal Proceedings of the National Academy of Sciences, the findings illuminate the indispensable role of ERRs in orchestrating mitochondrial growth and activity within muscle cells. This revelation positions ERRs as a highly promising avenue for drug development, offering hope to millions worldwide grappling with chronic fatigue and muscle weakness stemming from metabolic dysfunction.
The Silent Crisis of Cellular Energy: Mitochondria Under Siege
At the very core of our existence, within every cell of our bodies, reside tiny, bean-shaped powerhouses called mitochondria. These critical organelles are responsible for converting the food we consume into adenosine triphosphate (ATP), the usable energy currency that fuels virtually every biological process. This cellular-level metabolism is particularly vital in muscle cells, which demand a constant, robust supply of energy to power movement, from the simplest blink to strenuous athletic performance.
However, the efficiency of these cellular energy factories is often compromised. A significant portion of the population faces the challenge of dysfunctional mitochondria, a condition that can manifest in various forms and at different life stages. Roughly 1 in 5,000 individuals are born with primary mitochondrial diseases, severe genetic disorders that can affect multiple organ systems. Beyond these congenital conditions, countless others develop metabolic dysfunction later in life, a pervasive problem intimately linked with the aging process and a host of chronic diseases. The spectrum of conditions associated with impaired mitochondrial function is vast and alarming, encompassing severe neurodegenerative disorders like multiple sclerosis (MS) and dementia, cardiovascular ailments such as heart disease, and even the metabolic shifts observed in various cancers. The collective burden of these diseases underscores the urgent need for effective therapeutic interventions that can restore cellular energy balance.
Despite the widespread impact of mitochondrial dysfunction, treatment options have historically been limited and often focus on symptom management rather than addressing the root cause. This long-standing therapeutic void has driven researchers worldwide to seek novel strategies to bolster mitochondrial health and metabolic efficiency. It is against this backdrop of unmet medical need that the Salk Institute’s latest findings emerge as a beacon of hope.
A Decades-Long Quest: Unveiling the Power of Estrogen-Related Receptors
The recent findings from the Salk Institute pinpoint a group of proteins, the estrogen-related receptors, as a novel and remarkably effective therapeutic target. The Salk scientists, building upon decades of foundational research, discovered that these receptors play a profoundly important role in muscle cell metabolism, particularly under conditions of increased energy demand, such as during exercise. Their research demonstrates that ERRs possess the remarkable ability to both increase the sheer number of mitochondria within muscle cells and enhance their energetic output, thereby directly addressing the core issue of energy deficiency.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," explains senior author Ronald Evans, a distinguished professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Professor Evans’s connection to these receptors runs deep, tracing back to a landmark period in molecular biology. "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’s statement not only highlights the significance of the current discovery but also reflects a long and tenacious scientific journey. In the 1980s, his pioneering work led to the landmark discovery of an entire family of proteins, which he aptly named "nuclear hormone receptors." These extraordinary proteins function as molecular switches, capable of binding to specific hormones and then attaching themselves directly to our DNA. Upon binding, they regulate which genes get turned "on" or "off," thereby controlling a vast array of biological processes, from development and metabolism to reproduction and immunity. The discovery revolutionized our understanding of how hormones exert their profound effects on the body.
Estrogen-related receptors emerged as a distinct branch of this expansive nuclear hormone receptor family. Initially, their exact biological roles remained somewhat enigmatic due to their structural similarity to classic estrogen receptors but a lack of direct estrogen binding. However, their consistent presence in organs with high energy demands—such as the heart, brain, and kidneys—provided crucial clues. This physiological distribution strongly suggested that ERRs might play a fundamental role in regulating cellular energy metabolism. This intriguing observation precisely inspired Evans’s team to delve deeper and explore their potential regulatory function in another high-energy organ: skeletal muscle.
The Muscle-Mitochondria Connection: Exercise, Energy, and ERRs
Skeletal muscles are voracious consumers of energy, especially when called into action. The demands placed on muscle cells during physical activity are immense, requiring a rapid and sustained supply of ATP. In fact, exercise itself is one of the most potent natural signals for muscle tissue to trigger a process known as mitochondrial biogenesis. This vital adaptive mechanism involves a cell increasing the number of its mitochondria, effectively expanding its energy-producing capacity to meet heightened metabolic demands and facilitate recovery. For healthy individuals, regular exercise is a cornerstone of maintaining robust muscle function and overall metabolic health.
However, for a significant portion of the population, particularly those afflicted with muscular and metabolic disorders, engaging in meaningful exercise is often an insurmountable challenge. Conditions like muscular dystrophy, chronic fatigue syndrome, and various forms of myopathy leave individuals too weak or fatigued to undertake the physical activity necessary to stimulate mitochondrial biogenesis naturally. This critical limitation has spurred scientists to search for alternative, pharmacological pathways that could mimic the beneficial effects of exercise and stimulate mitochondrial growth and function without requiring physical exertion.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," elaborates first author Weiwei Fan, a staff scientist in Evans’s lab. Dr. Fan encapsulates the core hypothesis that guided their research: "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 foundational premise laid the groundwork for an ambitious experimental design aimed at uncovering the precise molecular machinery behind exercise-induced mitochondrial adaptation.
The Experimental Unveiling: Dissecting ERR Subtypes and Their Roles
To systematically investigate the potential role of estrogen-related receptors in muscle cell metabolism, Fan and his dedicated team embarked on a series of meticulous experiments using genetically modified mouse models. Their strategy involved selectively deleting different forms, or subtypes, of the estrogen-related receptors—specifically alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—within the muscle tissues of these mice. By observing the resulting physiological and cellular effects, they could precisely delineate the contribution of each ERR subtype to muscle function and mitochondrial health.
The initial findings provided crucial insights into the hierarchical and compensatory roles of these receptors. The researchers observed that ERRα was the most abundant subtype in muscle tissue, leading them to hypothesize its primary importance. Surprisingly, however, the loss of ERRα alone had only mild impacts on muscle tissue under normal, resting conditions. This unexpected resilience suggested that other mechanisms might be compensating for the absence of the dominant alpha subtype.
Further investigation revealed the crucial compensatory role of ERRγ. Despite making up a mere 4% of the total estrogen-related receptors, the gamma receptor demonstrated a remarkable ability to step in and compensate for the loss of ERRα under normal metabolic conditions. This finding highlighted the intricate interplay and redundancy built into the cellular regulatory machinery. However, the true significance of the ERRs became starkly evident when both the alpha and gamma types were simultaneously deleted. This dual deletion led to severe impairments in muscle mitochondrial activity, profound alterations in their shape and size, and a significant overall reduction in their functional capacity. This finding underscored that while ERRγ could partially compensate for ERRα, the combined absence of these two critical subtypes created an irreparable deficit in mitochondrial health.
The question then arose: If ERRα is so abundant, yet its sole deletion has only mild effects under normal conditions, what is its primary function? The team hypothesized that the abundance of ERRα was designed to enable muscles to adapt and grow in response to demanding physiological challenges, such as exercise. To test this hypothesis, the researchers put their mouse models through a regimen of voluntary exercise using mechanical wheels. This exercise challenge was designed to robustly trigger mitochondrial biogenesis in the muscle cells of the mice, allowing the researchers to assess whether ERRα was indeed involved in this critical adaptive process.
The results were unequivocal and striking: losing ERRα alone, even with ERRγ present, entirely blocked exercise-induced mitochondrial biogenesis. This groundbreaking finding provided a clear answer: while ERRγ could compensate for ERRα under resting conditions, ERRα was absolutely essential for the muscle’s ability to respond to and adapt to the metabolic stress of exercise by increasing its mitochondrial count. It cemented ERRα’s status as an indispensable driver of the muscle’s adaptive capacity.
The PGC1α Connection: ERRα as the "Druggable" Partner
The Salk team’s investigation didn’t stop at identifying ERRs as crucial players. They delved deeper into the molecular mechanisms, particularly focusing on how ERRs interact with other known regulators of mitochondrial function. Previous 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, playing a central role in coordinating gene expression related to energy metabolism.
However, a significant challenge with PGC1α as a direct therapeutic target for drug development lies in its mode of action. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to DNA or specific genes. Instead, it functions as a coactivator, meaning it relies entirely on partnering with other proteins, typically transcription factors, to exert its regulatory effects on gene expression. This indirect action makes PGC1α a more difficult molecule to target effectively with small-molecule drugs, which typically aim to directly modulate the activity of a specific receptor or enzyme.
The Salk lab’s subsequent analysis of muscle cells after exercise revealed the critical missing piece of the puzzle: PGC1α was partnering with ERRα to drive mitochondrial biogenesis. This partnership illuminated a crucial mechanistic link. The key difference, and the therapeutic advantage, lies in ERRα’s direct binding capability. Unlike its partner PGC1α, ERRα possesses the ability to bind directly to the promoters of mitochondrial energetic genes and actively turn them "on." This direct engagement with the genetic machinery makes ERRα a far more amenable and promising target for the development of therapeutic drugs designed to improve mitochondrial performance and energy output in muscle cells. By activating ERRα, scientists could potentially bypass the complexities of indirectly modulating PGC1α and directly stimulate the production of new, functional mitochondria.
A New Therapeutic Horizon: Systemic Benefits and Future Directions
The implications of this discovery are far-reaching and profoundly exciting. The Salk Institute’s findings suggest that developing a drug to specifically boost the activity of estrogen-related receptors, particularly ERRα, could be a powerful and effective way to restore energy supplies in people suffering from a wide array of metabolic disorders. This includes conditions like muscular dystrophy, a group of genetic diseases characterized by progressive muscle weakness and degeneration, for which current treatments are largely palliative.
"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 Dr. Fan. This statement underscores the systemic nature of metabolic health. Mitochondria are ubiquitous, and their dysfunction can ripple throughout the body, affecting multiple organ systems. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
This broader perspective opens up possibilities for addressing a spectrum of conditions beyond just skeletal muscle disorders. Enhanced mitochondrial function could potentially offer neuroprotective benefits for diseases like Alzheimer’s and Parkinson’s, where mitochondrial dysfunction is increasingly implicated. Similarly, improving energy metabolism in cardiac muscle could have significant implications for treating various forms of heart disease, where energy depletion often contributes to pathology. Even age-related decline, characterized by a general decrease in metabolic efficiency and energy levels, could potentially be mitigated by targeting ERRs.
Understanding precisely how estrogen-related receptors function in muscle cells creates unprecedented opportunities to develop therapies that can impact all parts of the body affected by mitochondrial dysfunction. The journey, however, is far from over. Future research will continue to delve deeper into the nuanced functions and complex regulation of both alpha- and gamma-type receptors. This ongoing investigation may uncover additional, subtype-specific therapeutic targets and refine our understanding of how best to harness the power of ERRs for clinical benefit. Researchers will also explore potential isoform-specific activators, investigate dose-response relationships, and meticulously assess any potential off-target effects to ensure the safety and efficacy of future drug candidates. Ultimately, the goal is to translate these exciting laboratory findings into tangible treatments that can significantly improve the quality of life for millions suffering from energy-depleting diseases.
This groundbreaking work was a testament to collaborative scientific endeavor, with a dedicated team contributing their expertise. 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 from the Salk Institute; Tae Gyu Oh from both Salk and the University of Oklahoma; and Christopher Liddle from the University of Sydney, Australia.
The research was generously supported by a consortium of prestigious institutions and foundations, underscoring the vital importance and high impact of this scientific pursuit. Key funding was provided 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. Their collective support was instrumental in bringing this transformative discovery to light, paving the way for a healthier, more energetic future.
About the Author
