LA JOLLA, CA – May 12, 2025 – In a breakthrough that could redefine the treatment landscape for a myriad of debilitating conditions, scientists at the Salk Institute have identified a crucial family of proteins, known as estrogen-related receptors (ERRs), as a pivotal mechanism for repairing energy metabolism and alleviating muscle fatigue. This groundbreaking discovery, published today in the prestigious Proceedings of the National Academy of Sciences, pinpoints ERRs as a promising therapeutic target for individuals suffering from mitochondrial dysfunction, muscle weakness, and fatigue associated with aging and chronic diseases.
The study illuminates how these receptors are indispensable drivers of mitochondrial growth and activity within muscle cells, particularly during physical exertion. By enhancing the number and energetic output of mitochondria, ERRs hold the potential to restore vital energy supplies in patients where current treatment options are limited and often ineffective. This research opens a new frontier in pharmacological intervention, offering hope to millions worldwide grappling with the silent but pervasive impact of metabolic disorders.
The Pervasive Crisis of Mitochondrial Dysfunction
At the very heart of cellular life, tiny, bean-shaped organelles called mitochondria serve as the body’s indispensable energy factories. They tirelessly convert the food we consume into adenosine triphosphate (ATP), the usable energy currency that powers every biological process, from thought to movement. This cellular-level metabolism is particularly critical in muscle cells, which demand vast quantities of fuel to support our daily activities and complex physical movements.
However, this intricate energy system is remarkably fragile. An estimated 1 in 5,000 individuals are born with congenital mitochondrial dysfunction, facing lifelong challenges that can range from mild fatigue to severe multi-system organ failure. Beyond these genetic predispositions, a significantly larger population develops metabolic dysfunction later in life. This acquired form is inextricably linked with the natural process of aging, but also emerges as a debilitating companion to a host of chronic diseases including cancer, multiple sclerosis (MS), heart disease, dementia, and various forms of muscular dystrophy.
The consequences of mitochondrial dysfunction are far-reaching and profoundly impact quality of life. Patients often experience chronic fatigue, muscle weakness, exercise intolerance, cognitive impairments, and increased susceptibility to other health complications. Despite its widespread prevalence and severe impact, effective treatments for mitochondrial dysfunction remain frustratingly elusive. Current therapeutic strategies often focus on symptom management or supportive care, rather than addressing the root cause of energy deficiency at the cellular level. This unmet medical need has driven relentless scientific inquiry into understanding and harnessing the body’s intrinsic energy regulation mechanisms.
Estrogen-Related Receptors: A New Frontier in Metabolic Repair
The recent findings from the Salk Institute represent a significant leap forward in this critical area of research. The Salk team has demonstrated that estrogen-related receptors (ERRs) play a crucial and previously underappreciated role in regulating muscle cell metabolism. Specifically, they discovered that these receptors are instrumental in dictating the quantity and efficiency of mitochondria, especially when muscles are under increased energy demand, such as during exercise.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," explains senior author Ronald Evans, professor and March of Dimes Chair in Molecular and Developmental Biology at Salk, whose laboratory led this seminal work. "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."
This insight into ERRs’ critical role suggests a novel therapeutic avenue: developing pharmacological agents that can specifically boost the activity of these receptors. Such a drug could potentially circumvent the challenges faced by individuals unable to exercise due to illness or frailty, offering a chemical means to stimulate the very cellular processes that keep us energized and mobile. The implications for conditions like muscular dystrophy, where muscle degeneration is coupled with severe energy deficits, are particularly profound.
The Genesis of a Discovery: Unraveling Nuclear Hormone Receptors
To fully appreciate the significance of this latest Salk breakthrough, it’s essential to understand the historical context of Ronald Evans’ pioneering work. The narrative of estrogen-related receptors begins decades ago with Evans’ landmark discovery in the 1980s of a vast family of proteins he aptly named "nuclear hormone receptors." This discovery fundamentally reshaped our understanding of how hormones exert their profound effects on the body.
Nuclear hormone receptors are a sophisticated class of proteins that act as molecular switches, responding to specific hormones (such as estrogens, androgens, thyroid hormones, and vitamin D) by binding directly to our DNA. Upon binding, they regulate the expression of specific genes, effectively turning them "on" or "off." This intricate gene regulation system orchestrates a myriad of biological processes, from development and reproduction to metabolism and immunity. Evans’ identification of this receptor family provided the foundational framework for understanding how hormones communicate with the genome, offering unprecedented insights into endocrine disorders and paving the way for targeted drug development.
Estrogen-related receptors (ERRs) represent a distinct and intriguing branch within this expansive family of nuclear hormone receptors. Unlike classic estrogen receptors, ERRs are not activated by estrogen itself, a characteristic that initially made their precise physiological function somewhat enigmatic. However, their pervasive presence in tissues with exceptionally high energy demands—such as the heart and the brain—provided compelling early clues. This observation ignited Evans’ team’s curiosity, prompting them to hypothesize that ERRs might play a specialized role in regulating metabolism within another high-energy organ: skeletal muscle. This intuition ultimately proved to be prescient, laying the groundwork for the current, pivotal discovery.
The Muscle’s Demand: Exercise, Energy, and Biogenesis
Skeletal muscle, constituting a substantial portion of our body mass, is a metabolically demanding tissue, particularly during physical activity. Every contraction, every movement, from the subtle twitch of an eyelid to the powerful lift of a weight, requires a constant and robust supply of ATP. This energy is predominantly generated by mitochondria. When we engage in exercise, our muscles’ energy requirements skyrocket, signaling a need for more efficient and abundant energy production.
In response to this increased demand, muscle cells initiate a remarkable adaptive process known as mitochondrial biogenesis. This biological phenomenon involves the synthesis of new mitochondrial proteins and lipids, leading to an increase in the number and overall mass of mitochondria within the cell. Essentially, the cell expands its energy factory capacity to meet heightened metabolic needs. This is why regular exercise improves endurance and reduces fatigue—it physically trains the muscles to become more efficient energy producers.
However, the very activity that stimulates this vital process—exercise—is often profoundly challenging, if not impossible, for individuals suffering from muscular and metabolic disorders. For patients with conditions like muscular dystrophy, severe fatigue, or advanced aging, the physical exertion required to trigger mitochondrial biogenesis can be too painful, too exhausting, or simply beyond their physical capabilities. This creates a vicious cycle: compromised energy production leads to weakness, which prevents exercise, thereby inhibiting the very mechanism that could improve their condition. Recognizing this critical barrier, scientists have been intensely searching for alternative, pharmacological strategies to stimulate mitochondrial biogenesis, offering a "workout in a pill" for those who cannot physically perform one.
"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 driving this phase of the 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 question propelled the Salk team into a meticulous investigation of ERRs’ precise role in muscle energy regulation.
Deciphering the ERR Code: Experimental Design and Key Findings
To systematically investigate the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues embarked on a series of carefully designed experiments utilizing genetically modified mouse models. Their approach involved selectively deleting different forms of these receptors within the muscle tissues of mice, allowing them to observe the resulting physiological and cellular effects. The three main forms of ERRs—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—were each targeted for deletion, either individually or in combination.
Their initial observations revealed intriguing complexities. They found that ERRα was the most abundantly expressed type of receptor in muscle tissue. However, surprisingly, the loss of ERRα alone had only mild impacts on muscle mitochondrial activity under normal, sedentary conditions. This led the researchers to investigate compensatory mechanisms. They discovered that ERRγ, despite making up a mere 4% of the total estrogen-related receptors, possessed a remarkable ability to compensate for the absence of ERRα, maintaining muscle mitochondrial function when ERRα was missing. This suggested a degree of redundancy or functional overlap among the ERR subtypes.
The true significance of ERRs became starkly evident when both ERRα and ERRγ were simultaneously deleted from muscle tissue. This dual deletion resulted in severe impairments in muscle mitochondrial activity, profoundly affecting their shape, size, and overall function. The mitochondria appeared dysfunctional and disorganized, underscoring the critical, non-redundant roles of these two receptor types in maintaining basal muscle energy health.
However, the question remained: why was ERRα so overwhelmingly abundant if its individual loss had only mild effects? The Salk team hypothesized that the answer lay in ERRα’s role during periods of heightened metabolic demand, specifically during exercise. To test this, they subjected their mice to an exercise regimen on mechanical wheels, a standard method for inducing mitochondrial biogenesis in muscle. This experiment yielded a dramatic and unequivocal result: losing ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. The muscles of ERRα-deficient mice failed to adapt and produce new mitochondria in response to physical activity, demonstrating ERRα’s indispensable role as a primary mediator of exercise-driven metabolic adaptation.
ERRalpha and PGC1alpha: A Synergistic Partnership
The scientific community has long recognized another protein, PGC1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body. PGC1α is known to orchestrate mitochondrial biogenesis and function in various tissues, including muscle. However, PGC1α presents a significant challenge for therapeutic drug development: unlike nuclear hormone receptors such as ERRs, PGC1α cannot directly bind to DNA and regulate gene expression on its own. It relies entirely on partner proteins to execute its functions, making it an indirect and therefore more difficult target for pharmacological intervention. Designing a drug that effectively modulates an indirect co-activator without unintended off-target effects is a complex endeavor.
This is where the Salk lab’s latest findings offer a crucial insight and a more actionable therapeutic strategy. When Evans’ team meticulously examined muscle cells after exercise, they discovered a critical molecular partnership: PGC1α was actively collaborating with ERRα to drive mitochondrial biogenesis. This revelation was a game-changer. While PGC1α is the "master switch," ERRα acts as the direct effector. Unlike PGC1α, ERRα possesses the inherent capability to bind directly to the DNA sequences of mitochondrial energetic genes and turn them "on." This direct binding ability positions ERRα as a far more promising and tractable target for therapeutic drug development. By activating ERRα, scientists could potentially bypass the complexities of PGC1α’s indirect action, offering a more direct and efficient pathway to improving muscle’s mitochondrial performance and overall energy metabolism.
Broad Horizons: Implications for Therapy and Beyond
The identification of estrogen-related receptors, particularly ERRα, as direct and indispensable drivers of mitochondrial growth and activity in muscle cells, carries profound implications for the future of medicine. This breakthrough opens up an entirely new avenue for the development of targeted therapies aimed at combating a wide spectrum of metabolic disorders and conditions characterized by muscle weakness and fatigue.
The most immediate and exciting implication is the potential for developing novel drugs designed to activate or boost the function of ERRs. Such pharmacological agents could act as molecular "exercise mimickers," stimulating mitochondrial biogenesis and enhancing energy production in individuals who are physically unable to exercise due to illness, injury, or advanced age. This could revolutionize the treatment of diseases such as muscular dystrophy, where progressive muscle wasting is compounded by severe energy deficits. By improving mitochondrial function, these drugs could potentially slow disease progression, alleviate debilitating fatigue, and significantly enhance muscle strength and endurance.
Beyond muscular dystrophy, the benefits of activating ERRs could extend to a multitude of other conditions where mitochondrial dysfunction plays a central role. This includes the widespread fatigue experienced by patients with cancer and multiple sclerosis, the age-related decline in muscle function (sarcopenia), and metabolic impairments seen in heart disease and certain forms of dementia. By restoring cellular energy balance, ERR-activating drugs could offer a holistic approach to improving patient outcomes across these diverse pathologies.
"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 potential of their discovery. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." The brain, being one of the most metabolically active organs, and the heart, a muscle that never rests, are particularly vulnerable to energy deficits. Enhancing mitochondrial function in these critical organs could offer protective effects against neurodegenerative diseases and cardiovascular pathologies.
While the promise is immense, the journey from laboratory discovery to clinical application is often long and complex. Future research will undoubtedly focus on several key areas. Scientists will continue to explore the nuanced functions and regulatory mechanisms of both alpha- and gamma-type receptors, seeking to understand their precise interplay and identify the most effective and specific ways to modulate their activity. This will involve delving deeper into the molecular pathways downstream of ERR activation and investigating potential off-target effects to ensure therapeutic specificity and safety. Identifying optimal drug candidates, conducting rigorous preclinical testing, and eventually initiating human clinical trials will be the next crucial steps in translating this groundbreaking scientific insight into tangible health benefits for patients.
The Salk Institute’s discovery of estrogen-related receptors as direct regulators of muscle energy metabolism represents a profound advance in our understanding of cellular bioenergetics. It illuminates a clear and actionable therapeutic pathway for conditions that have long defied effective treatment, offering a beacon of hope for millions struggling with the debilitating effects of mitochondrial dysfunction and muscle fatigue.
Other authors 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 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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