By Billy Candra 
A groundbreaking study from the Salk Institute suggests that a group of proteins known as estrogen-related receptors (ERRs) could hold the key to restoring energy metabolism and alleviating muscle fatigue, offering a promising new therapeutic avenue for a range of debilitating conditions. The research, published on May 12, 2025, in the Proceedings of the National Academy of Sciences, pinpoints these receptors as indispensable drivers of mitochondrial growth and activity within muscle cells, particularly in response to energy demands like exercise.
The Pervasive Challenge of Metabolic Dysfunction
At the very core of our cellular function, tiny, bean-shaped organelles called mitochondria serve as the body’s energy factories, converting the food we consume into adenosine triphosphate (ATP), the usable energy currency for cellular processes. This cellular-level metabolism is critically important in muscle cells, which demand substantial fuel to power movement and sustain physical activity. However, disruptions to this fundamental process are far from uncommon.
Approximately 1 in 5,000 individuals are born with primary mitochondrial disease, a diverse group of genetic disorders that severely impair mitochondrial function from birth. Beyond these congenital conditions, millions more develop metabolic dysfunction later in life. This acquired dysfunction is frequently associated with the natural aging process, as well as with a spectrum of chronic diseases, including various cancers, neurodegenerative conditions like multiple sclerosis (MS) and dementia, and cardiovascular diseases such as heart failure. The global prevalence of these conditions underscores the urgent need for effective treatments that target the root cause of energy deficits. For instance, according to the World Health Organization, non-communicable diseases, many of which involve metabolic irregularities, account for 74% of all deaths globally.
The symptoms of mitochondrial dysfunction are diverse and debilitating, ranging from profound muscle weakness and fatigue to neurological impairments, organ failure, and a reduced quality of life. Current treatments for these disorders are often limited to managing symptoms, highlighting a significant unmet medical need for therapies that can fundamentally restore cellular energy production.
A Legacy of Discovery: Dr. Ronald Evans and Nuclear Hormone Receptors
The recent Salk Institute findings build upon decades of pioneering research led by senior author Ronald Evans, a distinguished professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Dr. Evans has a long and illustrious history in the field of molecular biology, particularly renowned for his landmark discovery in the 1980s of a family of proteins he termed "nuclear hormone receptors."
These nuclear hormone receptors are a class of proteins found within cells that, upon binding to specific hormones (such as steroid hormones, thyroid hormones, or retinoids), translocate to the cell nucleus. Once in the nucleus, they attach themselves to specific DNA sequences, acting as transcription factors that regulate the expression of target genes. Essentially, they serve as molecular switches, turning genes "on" or "off" in response to hormonal signals, thereby controlling a vast array of physiological processes, including development, metabolism, and reproduction. This discovery revolutionized our understanding of how hormones exert their effects and opened up entirely new avenues for therapeutic intervention.
Among the various branches of this expansive family of nuclear hormone receptors are the estrogen-related receptors (ERRs). Dr. Evans’ lab was instrumental in discovering these receptors in 1988 and was among the first to recognize their potential, though initially less understood, role in energy metabolism. Unlike classic estrogen receptors, which bind to estrogen and mediate its traditional hormonal effects, ERRs do not bind to estrogen. Despite their structural similarity and nomenclature, ERRs function independently of estrogen, leading to early challenges in deciphering their precise physiological roles. Their widespread presence in metabolically active tissues, such as the heart, brain, and skeletal muscle—organs with high energy demands—intrigued Evans’ team and spurred further investigation into their specific contributions to cellular energy regulation.
Unveiling the Estrogen-Related Receptors (ERRs): A New Therapeutic Frontier
The recent study by Evans and his team specifically focused on the role of ERRs in skeletal muscle, a tissue characterized by its significant energy requirements, particularly during physical activity. Skeletal muscles are not only responsible for movement but also play a crucial role in whole-body metabolism, influencing glucose uptake and energy expenditure.
Exercise is a potent physiological signal that triggers mitochondrial biogenesis—the process by which cells increase the number and mass of their mitochondria to meet heightened energy demands. This adaptive response is vital for improving endurance and muscle performance. However, for individuals suffering from muscular and metabolic disorders, or those weakened by aging or disease, the ability to exercise sufficiently to induce these beneficial changes is severely compromised or even impossible. This limitation has driven scientists to seek pharmacological strategies that can mimic the effects of exercise and stimulate mitochondrial biogenesis independently of physical exertion.
"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 fundamental question guided the team’s experimental design.
The Study’s Design and Key Findings in Skeletal Muscle
To elucidate the precise role of ERRs in muscle cell metabolism, Fan and his colleagues conducted a series of meticulously designed experiments using mouse models. They genetically engineered mice to selectively delete specific forms of estrogen-related receptors within their muscle tissues. There are three main isoforms of ERRs: alpha (ERRα), beta (ERRβ), and gamma (ERRγ). By observing the resultant physiological effects of these deletions, the researchers aimed to pinpoint the individual and synergistic contributions of each receptor type.
Their initial findings revealed a complex interplay between the different ERR isoforms. While ERRα was found to be the most abundant type of receptor 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 mechanisms at play. Intriguingly, the researchers discovered that the gamma receptor (ERRγ), despite constituting a mere 4% of the total ERR population, was capable of largely compensating for the loss of ERRα under these standard conditions. This indicated a crucial, albeit minor in quantity, role for ERRγ in maintaining baseline mitochondrial function.
However, the picture changed dramatically when both the alpha and gamma types of ERRs were simultaneously deleted. This dual deletion led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size, and ultimately compromising their ability to produce energy. This finding underscored the critical, albeit partially redundant, roles of ERRα and ERRγ in maintaining robust mitochondrial function in muscle.
The researchers then turned their attention to the specific context of exercise. They hypothesized that the apparent excess of ERRα might serve a specialized function, particularly in enabling muscles to adapt and grow in response to physical demands. To test this, they subjected their mice to exercise regimens on mechanical wheels. This exercise paradigm is a well-established method for inducing mitochondrial biogenesis in muscle tissue, allowing the researchers to assess ERRα’s involvement in this adaptive process. The results were striking: the loss of ERRα alone completely blocked exercise-induced mitochondrial biogenesis. This pivotal finding established ERRα as an indispensable driver of the muscle’s capacity to generate new mitochondria in response to increased energy demands.
ERRα: A "Druggable" Target Beyond PGC1α
Previous research had identified another protein, PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body. PGC1α is known to play a central role in coordinating mitochondrial biogenesis and function in various tissues. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to DNA to regulate gene expression. Instead, it functions as a coactivator, meaning it must partner with other proteins, typically transcription factors, to exert its effects. This indirect mechanism makes PGC1α a more difficult target for designing small-molecule drugs that can directly modulate its activity.
The Salk team’s further investigation into muscle cells post-exercise revealed a crucial connection: PGC1α was found to be partnering with ERRα to drive mitochondrial biogenesis. This partnership is highly significant because, unlike PGC1α, ERRα possesses the ability to bind directly to the DNA sequences of mitochondrial energetic genes and activate their expression. This direct action makes ERRα a far more "druggable" target for pharmacological intervention. By developing a drug that specifically activates or modulates ERRα, scientists could potentially bypass the complexities of targeting PGC1α and directly enhance mitochondrial performance in muscle cells.
"Our lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism," says Dr. Evans. "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 statement encapsulates the culmination of decades of research, moving from initial discovery to a profound understanding of physiological function and therapeutic potential.
Broader Implications and Future Therapeutic Avenues
The implications of these findings extend far beyond addressing localized muscle fatigue. As Weiwei Fan notes, "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. Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
The heart, a continuously working muscle, and the brain, which consumes a disproportionately large amount of the body’s energy, are particularly vulnerable to mitochondrial dysfunction. Conditions like heart failure, neurodegenerative diseases, and even cognitive decline associated with aging could potentially benefit from therapies that enhance mitochondrial function via ERR activation. For instance, in conditions like Duchenne muscular dystrophy, where muscle degeneration is progressive and severe, a treatment that can boost energy production and mitochondrial resilience could significantly improve patient outcomes and slow disease progression.
The next steps in this promising research involve the meticulous development of specific ERRα activators. This process will entail high-throughput screening of chemical compounds, followed by rigorous testing for efficacy, specificity, and safety in preclinical models. While the prospect of a "drug to boost estrogen-related receptors" is exciting, the journey from laboratory discovery to clinical application is often long and complex, requiring extensive clinical trials to ensure both effectiveness and minimal side effects in human patients. Researchers will also continue to explore the nuanced functions and regulatory mechanisms of both alpha- and gamma-type receptors, which may unveil additional therapeutic targets or strategies for synergistic treatments.
This research highlights the Salk Institute’s ongoing commitment to fundamental biological discovery and its translation into tangible health benefits. By unraveling the intricate mechanisms of cellular energy regulation, the team has opened a significant new frontier in the fight against a wide array of metabolic disorders that diminish the quality of life for millions worldwide. The prospect of a pharmacological intervention that can effectively mimic the beneficial effects of exercise at a cellular level offers a beacon of hope for patients who currently have limited therapeutic options.
The comprehensive work was supported by a consortium of prestigious funding bodies, 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. Contributing authors included 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, underscoring the collaborative and interdisciplinary nature of this pivotal scientific endeavor.