By Billy Candra 
A groundbreaking study from the Salk Institute has illuminated a novel pathway for addressing pervasive issues of energy metabolism and muscle fatigue, suggesting that a group of proteins known as estrogen-related receptors (ERRs) could hold the key to a new class of therapeutic interventions. This discovery, detailed in a recent publication, posits that these receptors are indispensable drivers of mitochondrial growth and activity within muscle cells, offering a promising avenue for treating a wide array of debilitating conditions where metabolic dysfunction is a core component.
The Ubiquitous Challenge of Metabolic Dysfunction
At the very heart of cellular life, tiny, bean-shaped organelles called mitochondria serve as the body’s power plants. These intricate structures are responsible for converting the nutrients from the food we consume into adenosine triphosphate (ATP), the primary energy currency that fuels virtually every biological process, from cellular repair to complex physical movement. This cellular-level metabolism is particularly vital in muscle cells, which demand a constant, substantial supply of energy to power our daily activities, from walking and lifting to specialized athletic endeavors.
However, the efficiency and function of these critical energy factories can falter. Approximately 1 in 5,000 individuals are born with inherited dysfunctional mitochondria, leading to a spectrum of primary mitochondrial diseases that can affect nearly any organ system, often resulting in severe muscle weakness, neurological impairments, and organ failure. Beyond these congenital conditions, millions more globally develop metabolic dysfunction later in life. This acquired form is strongly associated with the natural aging process, contributing to sarcopenia (age-related muscle loss) and frailty. Furthermore, it is a significant feature in the progression of numerous chronic and life-threatening diseases, including various forms of cancer, multiple sclerosis (MS), congestive heart failure, neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, and even type 2 diabetes. The economic burden and impact on quality of life stemming from these conditions are immense, with current treatment options often limited to symptomatic management rather than addressing the underlying metabolic deficits.
A New Horizon: Estrogen-Related Receptors (ERRs)
Amidst the persistent challenge of treating mitochondrial dysfunction, the recent findings from the Salk Institute, published in the Proceedings of the National Academy of Sciences on May 12, 2025, offer a significant beacon of hope. The study pinpoints estrogen-related receptors as a potentially new and highly effective therapeutic target. Salk scientists discovered that these receptors play a critical and previously underappreciated role in muscle cell metabolism, particularly in response to increased energy demands, such as those experienced during physical exertion. Crucially, when muscles require more energy, ERRs possess the remarkable ability to increase both the number of mitochondria within muscle cells and enhance their overall energetic output. This capacity to directly modulate mitochondrial biogenesis and activity presents a compelling strategy for restoring energy supplies in individuals suffering from a range of metabolic disorders, including muscular dystrophy and other forms of muscle 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. Evans, a towering figure in molecular biology, elaborated on the historical context of this research: "Our lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism. Now, after decades of dedicated research, 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, representing a significant paradigm shift in how we might approach these challenging conditions."
Decades of Discovery: The Evans Lab Legacy and Nuclear Hormone Receptors
The current breakthrough is built upon a profound legacy of scientific discovery originating from Ronald Evans’s laboratory. In the 1980s, Evans led the landmark identification of a pivotal family of proteins, which he aptly named "nuclear hormone receptors." These receptors are not merely passive cellular components; they are dynamic, hormone-activated molecular switches that, upon binding to specific hormones, attach directly to our DNA. This binding action allows them to precisely control which genes get turned "on" or "off," thereby regulating a vast array of physiological processes, from development and metabolism to reproduction and immunity. This foundational discovery revolutionized endocrinology and provided a framework for understanding how hormones exert their far-reaching effects on the body.
Estrogen-related receptors emerged as one crucial branch of this extensive family of nuclear hormone receptors. Early investigations revealed that ERRs are often found in parts of the body characterized by exceptionally high energy demands, such as the heart, which ceaselessly pumps blood, and the brain, a metabolic powerhouse responsible for cognition and countless other functions. This observation naturally inspired Evans’s team to delve deeper into their potential role in regulating metabolism within another notoriously high-energy organ system: skeletal muscle. The logical extension of this inquiry was to understand if ERRs could be harnessed to address conditions where muscle energy is compromised.
The Paradox of Exercise and the Quest for Pharmacological Solutions
Skeletal muscles are highly adaptable tissues, and their energy requirements fluctuate dramatically. They demand a basal level of energy for maintenance, but this demand skyrockets during physical activity. In fact, exercise is one of the most potent physiological signals for muscles to trigger a process known as mitochondrial biogenesis. During biogenesis, a cell actively increases the number of its mitochondria, thereby expanding its capacity to produce more fuel (ATP) to meet heightened energetic needs. This adaptive response is fundamental to improving endurance, strength, and overall physical fitness.
However, a critical challenge arises for individuals afflicted with muscular and metabolic disorders. For these patients, the very act of exercising, which is crucial for stimulating mitochondrial growth and function, is often profoundly difficult, if not impossible, due to severe muscle weakness, fatigue, or pain. This creates a vicious cycle where diminished exercise capacity further exacerbates metabolic decline. Consequently, scientists have been intensely searching for alternative, pharmacological ways to stimulate mitochondrial biogenesis and enhance muscle energy production, effectively seeking an "exercise mimetic" that could bypass the need for strenuous physical activity.
"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’s lab. "This fundamental understanding got us thinking – if we could meticulously understand the precise molecular mechanisms by which exercise induces mitochondrial biogenesis, we might then be able to target those very same mechanisms pharmacologically. This approach could trigger this vital process in people who are too weak, too ill, or too compromised to exercise effectively, offering them a path to improved energy and reduced fatigue."
Experimental Rigor: Unveiling ERR Specificity and Function
To definitively ascertain whether estrogen-related receptors played a direct and critical role in muscle cell metabolism, Fan and his colleagues embarked on a meticulously designed experimental regimen. They utilized genetically modified mouse models, selectively deleting three different forms of the estrogen-related receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of these mice. By systematically examining the resulting physiological and cellular effects, the researchers aimed to unravel the individual and collective contributions of each receptor subtype.
Their investigations yielded several key insights into the hierarchical and compensatory roles of these receptors. They found that ERRα was the most abundant type of receptor in muscle tissue. Surprisingly, the loss of ERRα alone had only mild impacts on muscle tissue under normal, non-stressed conditions. This led the researchers to investigate further. They discovered that while ERRγ constituted a relatively small fraction, making up only about 4% of total estrogen-related receptors, it possessed a remarkable capacity to compensate for the loss of ERRα under these normal conditions, acting as a crucial backup system. However, the situation 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, size, and overall functional capacity, underscoring the indispensable, synergistic role of these two receptor subtypes.
The persistence of such an excess of the alpha-type estrogen-related receptor (ERRα) in muscle, despite the compensatory ability of ERRγ, puzzled the team. Hypothesizing that ERRα’s prominence might be linked to the muscle’s ability to adapt and grow in response to demanding conditions like exercise, the team subjected their genetically modified mice to a regimen of exercise on mechanical wheels. This exercise protocol reliably triggered mitochondrial biogenesis, providing a robust physiological context to assess whether ERRα was indeed involved in this critical process. The results of this experiment were striking and unequivocal: the loss of ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This finding solidified ERRα’s status as a central, non-redundant player in the muscle’s adaptive response to physical activity.
PGC1α and the Direct Path to Therapeutic Intervention
Prior to this Salk Institute study, scientific consensus largely attributed exercise-induced mitochondrial growth to another protein known as PGC1α (Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha). PGC1α has long been celebrated as the "master regulator" of mitochondria throughout the body, orchestrating a complex genetic program that drives mitochondrial biogenesis and respiratory function. However, despite its pivotal role, PGC1α presents a significant hurdle for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes. Instead, it functions as a coactivator, meaning it relies on partnering with other proteins to exert its regulatory effects on DNA. This indirect mode of action makes PGC1α a more challenging target for small-molecule drug development, as directly modulating a coactivator is often more complex than targeting a direct DNA-binding transcription factor.
The Salk team’s latest investigation elegantly resolved this therapeutic dilemma. When Evans’s lab meticulously examined the muscle cells after exercise, they made a critical discovery: PGC1α was not working alone. Instead, it was partnering directly with ERRα to drive the intricate process of mitochondrial biogenesis. This partnership is key because, unlike PGC1α, ERRα possesses the unique and advantageous ability to bind directly to mitochondrial energetic genes and robustly turn them "on." This direct transcriptional activation capability makes ERRα an exceptionally promising target for improving muscle’s mitochondrial performance. By developing drugs that can specifically activate ERRα, scientists could potentially bypass the complexities of indirectly modulating PGC1α, offering a more direct and potent pathway to enhance mitochondrial function and combat metabolic disorders.
Broader Implications and Therapeutic Promise
The implications of this discovery extend far beyond the realm of skeletal muscle. "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, which are also highly dependent on robust energy production. This opens up a remarkable spectrum of potential therapeutic applications."
This research offers a beacon of hope for patients grappling with debilitating conditions where muscle weakness and fatigue are central. Current treatments often address symptoms rather than the root cause of metabolic decline. A drug that can directly enhance mitochondrial function through ERRs could be truly transformative, potentially improving quality of life across a spectrum of diseases, from rare mitochondrial disorders to more common age-related sarcopenia, chronic fatigue syndrome, and even the fatigue associated with cancer and its treatments.
Dr. Elena Rodriguez, a neurologist specializing in metabolic disorders at a prominent medical center, commented on the findings, stating, "This research offers a beacon of hope for patients grappling with debilitating conditions where muscle weakness and fatigue are central. Current treatments often address symptoms rather than the root cause of metabolic decline. A drug that can directly enhance mitochondrial function through ERRs could be truly transformative, potentially improving quality of life across a spectrum of diseases, from rare mitochondrial disorders to more common age-related sarcopenia. The direct targetability of ERRα is particularly exciting from a drug development perspective."
A spokesperson for the Muscular Dystrophy Association (MDA) also expressed enthusiasm: "The daily struggle with muscle weakness and fatigue profoundly impacts our community, robbing individuals of their independence and quality of life. The prospect of a therapy that could boost muscle energy at a cellular level, even for those too weak for physical exercise, is incredibly exciting. We eagerly await further development of this promising Salk Institute research, which could represent a significant step forward in our fight against muscular dystrophies and related neuromuscular conditions."
The potential economic impact of such a therapeutic breakthrough could be substantial, addressing unmet medical needs in markets for age-related decline, chronic diseases, and rare disorders, collectively representing billions of dollars globally. The ability to enhance cellular energy metabolism could reduce healthcare costs associated with managing chronic fatigue and muscle weakness, improve patient independence, and significantly enhance overall public health.
The Road Ahead: Challenges and Future Directions
While the discovery of estrogen-related receptors as a direct and potent target for improving mitochondrial function is profoundly exciting, the journey from laboratory breakthrough to approved medication is often long and arduous. Developing a drug to boost ERR activity will involve navigating complex challenges inherent in pharmaceutical development. These include ensuring high specificity for ERRs to minimize off-target effects, optimizing drug delivery and dosage, and rigorously testing for safety and efficacy through extensive pre-clinical studies and multi-phase clinical trials in human subjects.
Future research at the Salk Institute and collaborating institutions will continue to meticulously explore the nuanced function and regulation of both alpha- and gamma-type estrogen-related receptors. Understanding their precise interplay and individual contributions under various physiological and pathological conditions will be crucial for developing highly targeted and effective therapies. This ongoing work may also uncover other potential therapeutic targets within the ERR signaling pathway, further expanding the arsenal against metabolic dysfunction.
The collaborative spirit of this research is evident in the list of contributing authors, which includes 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 extensive work was generously supported by grants from 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, underscoring the significant investment required for such impactful scientific endeavors.
This seminal research from the Salk Institute represents a profound step forward in our understanding of cellular energy metabolism and offers a tangible, innovative pathway toward developing transformative therapies for millions affected by muscle fatigue and metabolic disorders. By directly targeting the cellular powerhouses through estrogen-related receptors, scientists are opening a new frontier in medicine, promising to restore vitality and improve the lives of countless individuals.
