LA JOLLA, CA – May 12, 2025 – In a significant stride towards combating debilitating metabolic disorders and muscle fatigue, a groundbreaking study from the Salk Institute has pinpointed estrogen-related receptors (ERRs) as crucial regulators of energy metabolism in muscle cells. This discovery, detailed in the Proceedings of the National Academy of Sciences, offers a promising new therapeutic avenue for a wide array of conditions ranging from muscular dystrophy to age-related frailty, and chronic diseases like multiple sclerosis and heart disease.
The research suggests that by activating these specific receptors, scientists could potentially restore vital energy supplies and enhance mitochondrial function, thereby alleviating muscle weakness and fatigue that plague millions worldwide. The findings illuminate a previously underappreciated mechanism by which our bodies generate and utilize energy, particularly within the highly demanding environment of skeletal muscle.
The Ubiquitous Energy Crisis: Understanding Mitochondrial Dysfunction
At the core of all living cells lie mitochondria, often dubbed the "powerhouses of the cell." These tiny, bean-shaped organelles are responsible for converting the food we consume into adenosine triphosphate (ATP), the primary energy currency that fuels virtually every cellular process. This intricate cellular-level metabolism is paramount in muscle cells, which demand copious amounts of energy to facilitate movement, maintain posture, and perform strenuous activities.
However, the efficiency of this vital energy production system is frequently compromised. Globally, an estimated 1 in 5,000 individuals are born with primary mitochondrial diseases, genetic disorders that lead to dysfunctional mitochondria from birth. Beyond these congenital conditions, a far greater number of people develop metabolic dysfunction later in life. This acquired impairment is intimately linked with the natural process of aging, contributing to the decline in physical strength and endurance characteristic of sarcopenia and frailty. Moreover, mitochondrial dysfunction is a pervasive underlying factor in numerous chronic and debilitating diseases, including various cancers, neurodegenerative disorders such as Alzheimer’s and Parkinson’s, multiple sclerosis (MS), cardiovascular diseases, and even mental health conditions.
The clinical manifestations of mitochondrial dysfunction are diverse and often severe, ranging from profound muscle weakness and chronic fatigue to neurological deficits, cardiac issues, and impaired organ function. Diagnosing these conditions can be challenging due to their varied presentations, and effective treatments remain largely elusive. Current therapeutic strategies primarily focus on managing symptoms and supportive care, highlighting an urgent need for novel interventions that can address the root cause of the energy deficit. The difficulty in treating these conditions underscores the immense potential of the Salk Institute’s latest findings, which propose a direct pathway to revitalize cellular energy production.
A Historical Journey: The Discovery of Nuclear Hormone Receptors and ERRs
The path to understanding estrogen-related receptors traces back decades to the pioneering work of Professor Ronald Evans, a senior author of the current study and the March of Dimes Chair in Molecular and Developmental Biology at Salk. In the 1980s, Evans led the landmark discovery of a vast family of proteins he named "nuclear hormone receptors." These receptors are extraordinary cellular architects; when activated by specific hormones, they translocate to the cell nucleus, where they bind to distinct sequences of DNA. By doing so, they act as molecular switches, precisely controlling which genes are turned "on" or "off," thereby orchestrating a myriad of physiological processes, from development and metabolism to inflammation and reproduction. This foundational work revolutionized our understanding of how hormones exert their profound effects on the body and opened up entirely new fields of research in endocrinology and pharmacology.
Among the many branches of this intricate nuclear hormone receptor family are the estrogen-related receptors (ERRs). Structurally, ERRs bear a striking resemblance to classic estrogen receptors, which are well-known for mediating the widespread effects of the hormone estrogen throughout the body. However, despite their architectural similarity, the precise biological functions and ligand-binding characteristics of ERRs have historically been much less understood, earning them the moniker "orphan receptors" for a time. Professor Evans’ lab was among the first to identify ERRs in 1988 and quickly recognized their potential role in energy metabolism, particularly noting their high expression in tissues with high metabolic demands, such as the heart and the brain. This initial insight laid the groundwork for decades of subsequent research, culminating in the current detailed investigation into their indispensable role in skeletal muscle.
The Salk Study: A Deep Dive into ERR Function in Muscle
The profound energy requirements of skeletal muscle, especially during physical activity, served as the primary inspiration for Evans’ team to delve deeper into the role of ERRs in this high-energy organ. When we engage in exercise, our muscles demand significantly more fuel, prompting a crucial cellular adaptation known as mitochondrial biogenesis. This process involves the cell increasing both the number and the efficiency of its mitochondria to meet the heightened energy demands, effectively building more "energy factories."
However, for individuals grappling with muscular and metabolic disorders, or those weakened by aging or chronic illness, the very act of exercise – the most potent natural stimulus for mitochondrial biogenesis – is often prohibitively difficult, if not impossible. The pain, fatigue, and weakness associated with their conditions create a cruel paradox, preventing them from benefiting from the very activity that could improve their cellular energy production. This critical unmet need motivated the Salk scientists to seek alternative, pharmacological strategies that could mimic the beneficial effects of exercise.
"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. "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 compelling question formed the bedrock of their experimental design.
To systematically investigate the role of ERRs in muscle cell metabolism, Fan and his colleagues embarked on a meticulously designed study using genetically modified mouse models. They specifically targeted the deletion of three different forms, or subtypes, of estrogen-related receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – within the muscle tissues of these mice. By selectively removing these receptors, the researchers could observe the resulting physiological and metabolic consequences, thereby inferring the specific functions of each ERR subtype.
Their initial observations revealed intriguing insights into the hierarchy and compensatory mechanisms among the ERR subtypes. While ERRα was found to be the most abundant receptor type in muscle tissue, its isolated deletion had surprisingly mild impacts on muscle mitochondrial activity under normal, resting conditions. This suggested a degree of functional redundancy or compensatory action. Further investigation uncovered that ERRγ, despite constituting only a minor fraction (approximately 4%) of the total estrogen-related receptors, played a critical compensatory role. In the absence of ERRα, ERRγ was capable of stepping up to maintain muscle mitochondrial function, indicating a robust built-in failsafe mechanism. However, the picture changed dramatically when both ERRα and ERRγ were simultaneously deleted. This dual knockout resulted in severe impairments in muscle mitochondrial activity, significantly altering their shape and reducing their overall size. These findings strongly indicated that while ERRγ could compensate for ERRα deficiency to some extent, the combined absence of these two key receptors was devastating for muscle energy metabolism, underscoring their collective indispensable roles.
The researchers then turned their attention to the enigmatic abundance of ERRα. If ERRγ could compensate for its loss under normal conditions, why was ERRα so prevalent? The team hypothesized that ERRα’s true significance might emerge under conditions of heightened metabolic demand, specifically during exercise. To test this, they subjected their genetically modified mice to exercise regimens on mechanical wheels. This controlled exercise protocol served as a powerful physiological stimulus for mitochondrial biogenesis, allowing the researchers to directly assess whether ERRα was indeed a critical component of this exercise-induced adaptation. The results were conclusive: the loss of ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This striking finding confirmed that ERRα is not merely abundant but is an indispensable driver of the muscle’s adaptive response to physical activity, mediating the cellular growth of new mitochondria.
The Molecular Mechanism: ERRalpha as the Direct Regulator
The discovery of ERRα’s crucial role in exercise-induced mitochondrial biogenesis immediately brought to mind another well-established player in this process: PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α has long been recognized as a "master regulator" of mitochondria throughout the body, orchestrating their growth and function. Its activation is a known consequence of exercise, leading to a cascade of events that enhance cellular energy production.
However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α itself cannot directly bind to DNA and activate genes. Instead, it functions as a coactivator, meaning it must partner with other proteins – transcription factors – to exert its regulatory effects on gene expression. This indirect mode of action makes PGC1α a more difficult target for small-molecule drugs, as it requires modulating its interactions with multiple partners, a task far more complex than targeting a receptor that directly binds to DNA.
This distinction proved to be a pivotal insight for Evans’ lab. When they meticulously examined muscle cells after exercise, they discovered a crucial molecular partnership: PGC1α was indeed activated, but it was physically interacting with and coactivating ERRα to drive the process of mitochondrial biogenesis. This interaction revealed ERRα as the crucial direct link in the chain. Unlike PGC1α, ERRα possesses the inherent ability to bind directly to the DNA sequences of mitochondrial energetic genes and switch them "on." This direct gene-binding capability makes ERRα an exceptionally promising target for pharmacological intervention.
"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," says Professor Ronald Evans. "This makes them a really promising target to treat muscle weakness and fatigue in many different diseases that involve metabolic dysfunction." The ability to directly manipulate ERRα offers a more straightforward and potentially more effective strategy to pharmacologically induce the beneficial effects of exercise on mitochondrial health, bypassing the limitations of PGC1α-targeted approaches.
Broad Implications and Future Horizons
The implications of the Salk Institute’s findings extend far beyond the realm of skeletal muscle. While the study specifically focused on muscle cells, the principle that activating estrogen-related receptors can enhance mitochondrial function and energy metabolism suggests potential systemic benefits across the entire 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," emphasizes Weiwei Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." Given that mitochondria are ubiquitous in virtually every cell, enhancing their performance through ERR activation could profoundly impact tissues with high energy demands, such as the heart, which continuously pumps blood, and the brain, which processes vast amounts of information. This opens the door for potential therapeutic applications in conditions like heart failure, neurodegenerative diseases, and even cognitive decline associated with aging.
The immediate promise lies in developing novel therapeutics for a range of metabolic disorders and conditions characterized by muscle weakness and fatigue. For instance, individuals suffering from muscular dystrophies, a group of genetic diseases causing progressive muscle degeneration, could benefit immensely from drugs that boost mitochondrial activity and delay muscle wasting. Similarly, patients experiencing debilitating fatigue in chronic conditions like multiple sclerosis, cancer, or long COVID syndrome might find relief through ERR-activating compounds. Furthermore, the burgeoning challenge of age-related sarcopenia, the progressive loss of muscle mass and strength that affects quality of life in older adults, could be directly addressed by interventions that stimulate mitochondrial biogenesis and improve muscle performance.
However, the journey from laboratory discovery to clinical application is often long and complex. Future research will undoubtedly focus on several critical areas. A deeper understanding of the distinct functions and regulatory mechanisms of both alpha- and gamma-type estrogen-related receptors will be essential. While ERRα appears to be the primary driver of exercise-induced biogenesis, the compensatory role of ERRγ suggests a nuanced interplay that warrants further investigation. Scientists will also need to identify potent and selective small-molecule activators for these receptors, ensuring that any potential drug can specifically target the desired ERR subtypes without causing off-target effects. Rigorous preclinical testing will be necessary to evaluate the safety, efficacy, and optimal dosing of such compounds, followed by extensive clinical trials in human populations. Addressing challenges such as drug specificity, potential side effects, and long-term safety will be paramount in translating this exciting discovery into tangible clinical benefits.
Ultimately, the Salk Institute’s latest breakthrough represents a beacon of hope for millions affected by energy-related ailments. By uncovering the indispensable role of estrogen-related receptors in orchestrating muscle energy metabolism, this research has not only deepened our fundamental understanding of cellular biology but has also forged a clear and compelling path towards innovative therapeutic strategies that could one day restore vitality and improve the quality of life for countless individuals.
Collaborative Science and Support
The groundbreaking work was a testament to collaborative scientific effort. In addition to Professor Ronald Evans and Dr. Weiwei Fan, other key authors of the 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.
This research was made possible through the generous support of various esteemed organizations, including 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 commitment to advancing biomedical research is crucial for discoveries that push the boundaries of medical science and offer new hope for human health.
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