By Billy Candra 
LA JOLLA, CA – A groundbreaking study from the Salk Institute has illuminated a potential new pathway for treating metabolic dysfunction and muscle fatigue, identifying estrogen-related receptors (ERRs) as crucial regulators of cellular energy production. Published on May 12, 2025, in the esteemed journal Proceedings of the National Academy of Sciences, the research posits that developing therapeutic agents to boost ERR activity could offer a powerful strategy to restore energy supplies in individuals grappling with a spectrum of metabolic disorders, from muscular dystrophy to age-related decline.
Understanding the Energy Crisis: Mitochondrial Dysfunction Explained
At the very core of our biological functions lies cellular metabolism, a complex process primarily orchestrated by tiny, bean-shaped organelles known as mitochondria. Often referred to as the "powerhouses of the cell," mitochondria are responsible for converting the food we consume into adenosine triphosphate (ATP), the usable energy currency that fuels virtually every bodily process. This intricate energy generation is particularly vital in muscle cells, which demand substantial fuel to facilitate movement, maintain posture, and perform strenuous activities.
However, this critical system is vulnerable. Primary mitochondrial diseases, a group of genetic disorders, affect approximately 1 in 5,000 people, leading to a wide array of symptoms due to dysfunctional mitochondria. Beyond these congenital conditions, a much larger population develops metabolic dysfunction later in life. This acquired impairment is intimately linked with aging, where cellular energy production naturally declines, contributing to sarcopenia (age-related muscle loss) and general fatigue. Furthermore, a growing body of evidence connects metabolic dysfunction to a host of debilitating chronic diseases, including various forms of cancer, multiple sclerosis (MS), heart disease, neurodegenerative conditions like Alzheimer’s and Parkinson’s dementia, and metabolic syndromes such as type 2 diabetes. The global burden of these conditions is immense, with millions worldwide suffering from compromised quality of life and reduced physical capabilities directly attributable to impaired energy metabolism. For instance, according to the World Health Organization, non-communicable diseases, many with metabolic underpinnings, account for 71% of all deaths globally. The challenge of treating these diverse manifestations of mitochondrial dysfunction has long perplexed the medical community, primarily due to the ubiquitous nature of mitochondria and the complexity of their regulatory pathways.
A New Hope: Estrogen-Related Receptors (ERRs) Unveiled
Against this backdrop of unmet medical need, the Salk Institute’s latest findings offer a significant beacon of hope. The research, spearheaded by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology, has pinpointed a group of proteins known as estrogen-related receptors as a novel and potentially highly effective therapeutic target. The Salk team’s investigations revealed that ERRs play an indispensable role in the intricate machinery of muscle cell metabolism, a function that becomes particularly pronounced during periods of increased energy demand, such as exercise. Crucially, these receptors possess the capacity to not only increase the sheer number of mitochondria within muscle cells, a process known as mitochondrial biogenesis, but also to significantly enhance their energetic output, thereby boosting the cell’s overall fuel production capacity.
"Estrogen-related receptors bear a striking resemblance to classic estrogen receptors, yet their specific functions have remained less understood for decades," Professor Evans explained. "Our laboratory first identified estrogen-related receptors back in 1988, and we were among the first to recognize their profound involvement in energy metabolism. What we have now unequivocally established is that ERRs are absolutely essential drivers of both mitochondrial growth and activity within our muscles. This discovery positions them as an exceptionally promising target for addressing muscle weakness and the pervasive fatigue associated with numerous diseases characterized by metabolic dysfunction."
The Salk Institute’s Legacy: Pioneering Nuclear Hormone Receptor Research
The current breakthrough is built upon a foundational legacy of scientific inquiry established by Professor Evans and his team. In the 1980s, a period marked by rapid advancements in molecular biology, Evans led the seminal discovery of a vast family of proteins that he aptly named "nuclear hormone receptors." These receptors represent a sophisticated class of molecular switches that, upon activation by specific hormones or other signaling molecules, bind to our DNA and precisely control the expression of genes—turning them "on" or "off." This regulatory mechanism underpins a myriad of physiological processes, from development and reproduction to metabolism and immune response.
Estrogen-related receptors constitute a distinct branch within this expansive family of nuclear hormone receptors. Their ubiquitous presence and high concentration in organs with significant energy demands, such as the heart and the brain, naturally piqued Evans’ team’s interest in exploring their potential regulatory role in another metabolically active organ: skeletal muscle. The logical inference was that if ERRs were prevalent in other high-energy tissues, they likely played a comparable, if not critical, role in muscle energetics.
Decoding Muscle Metabolism: The Role of Exercise and ERRs
Skeletal muscles are prodigious consumers of energy, a demand that escalates dramatically during physical exertion. Indeed, exercise is one of the most potent physiological signals that triggers mitochondrial biogenesis in muscle cells. This adaptive process allows muscles to generate more mitochondria, thereby increasing their capacity to produce the necessary fuel for sustained activity and recovery. However, this natural mechanism presents a cruel paradox for individuals afflicted with muscular and metabolic disorders. For patients suffering from conditions like muscular dystrophy, chronic fatigue syndrome, or even severe sarcopenia, the ability to engage in meaningful exercise is severely compromised or entirely absent. This physical limitation means they cannot harness exercise’s inherent power to stimulate mitochondrial growth and improve energy production, perpetuating a cycle of weakness and fatigue. Recognizing this critical barrier, scientists have long sought alternative, pharmacological avenues to stimulate mitochondrial biogenesis in these vulnerable populations.
"Mitochondria function as the primary energy factories within our cells; consequently, the more intensely we exercise, the greater the demand for mitochondria our muscles require," noted first author Weiwei Fan, a staff scientist in Evans’ laboratory. "This observation led us to a pivotal question: if we could precisely understand the molecular mechanisms by which exercise induces mitochondrial biogenesis, could we then pharmacologically target those very same mechanisms? This would allow us to therapeutically trigger this essential process in individuals who are simply too weak or too ill to exercise effectively."
To rigorously test the hypothesis that estrogen-related receptors play a central role in muscle cell metabolism, Fan and his colleagues embarked on a meticulously designed experimental regimen. They genetically deleted three distinct forms of these receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of laboratory mice. Subsequently, they carefully examined the resultant physiological and cellular effects.
The Alpha and Gamma Partnership: Unraveling ERR Dynamics
Their investigations yielded several key insights into the hierarchical and compensatory roles of the different ERR subtypes. They observed that ERRα was the most abundant type of receptor present in muscle tissue. However, surprisingly, the isolated loss of ERRα alone had only relatively mild impacts on muscle tissue function under normal, sedentary conditions. This intriguing observation led them to further explore the roles of the other subtypes. They discovered that ERRγ, despite constituting a comparatively small fraction—only about 4%—of the total estrogen-related receptors, possessed a remarkable capacity to compensate for the absence of ERRα under baseline physiological conditions. This suggested a degree of functional redundancy or a backup system within the ERR family.
The critical nature of these receptors became starkly evident when both the alpha and gamma types were simultaneously deleted. This dual knockout resulted in profound and serious impairments in muscle mitochondrial activity, severely altering their shape and size. These findings underscored that while ERRα might be the primary player, ERRγ provides a crucial safety net, ensuring metabolic stability in its absence.
Given the apparent redundancy, the researchers then posed a fundamental question: why does the alpha-type estrogen-related receptor (ERRα) exist in such abundant quantities if its singular loss has only mild effects? They hypothesized that the answer lay in the muscle’s adaptive response to increased energy demands, specifically exercise. To test this, the team subjected their genetically modified mice to exercise on mechanical wheels. This regimen was designed to trigger mitochondrial biogenesis, allowing the researchers to directly assess ERRα’s involvement in this exercise-induced adaptive process. The results were conclusive and striking: the specific loss of ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This finding solidified ERRα’s critical, non-redundant role in the muscle’s ability to adapt and grow its energy infrastructure in response to physical activity.
Targeting the Master Regulator: Why ERRs Stand Out
Prior scientific investigations had established that exercise-induced mitochondrial growth was largely orchestrated by another pivotal protein known as PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α has long been recognized as a "master regulator" of mitochondria throughout the entire body, playing a central role in metabolic programming. However, PGC1α presents a significant challenge from a therapeutic drug development perspective. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot directly bind to genes in the DNA to regulate their expression. Instead, it functions as a coactivator, meaning it must rely on partnering with other proteins—transcription factors—to exert its effects. This indirect mode of action makes PGC1α a considerably more difficult target for the development of small-molecule drugs, as it lacks a direct binding site that can be readily modulated.
The Salk laboratory’s subsequent examination of muscle cells after exercise provided the missing piece of the puzzle. They discovered that PGC1α was indeed partnering with ERRα to drive the process of mitochondrial biogenesis. However, unlike PGC1α, ERRα possesses the crucial ability to directly bind to the specific "mitochondrial energetic genes" and activate them, effectively turning them "on." This direct binding capability makes ERRα an exceptionally attractive and promising target for pharmacological intervention aimed at improving muscle’s mitochondrial performance. The potential to directly modulate ERRα offers a more straightforward and efficient pathway for drug development compared to the indirect modulation of PGC1α.
Broader Horizons: Systemic Benefits and Future Implications
The implications of these findings extend far beyond the realm of muscle function. "Our findings strongly suggest that activating estrogen-related receptors could not only provide critical fuel for people’s muscles but could also yield a cascade of other beneficial effects across the entire body," stated Fan. "Improving fundamental mitochondrial function and enhancing overall energy metabolism has the potential to strengthen a multitude of different organ systems, including vital ones like the brain and the heart, which are also highly energy-dependent."
Mitochondrial dysfunction is a common denominator in many chronic diseases affecting these organs. In the heart, impaired mitochondrial function contributes to heart failure and cardiomyopathy. In the brain, it is implicated in neurodegenerative diseases and cognitive decline. Therefore, a therapeutic strategy that boosts ERR activity could theoretically offer systemic benefits, improving the health and resilience of these critical organs. For patients with conditions like muscular dystrophy, where progressive muscle degeneration is accompanied by systemic weakness, such a broad-acting therapeutic could be transformative. Similarly, for individuals battling chronic fatigue syndromes, age-related energy deficits, or even the metabolic side effects of cancer treatments, a drug targeting ERRs could represent a significant step forward in restoring vitality and improving quality of life.
The Road Ahead: From Discovery to Therapy
While the Salk Institute’s discovery marks a significant leap forward, the journey from laboratory finding to a widely available therapeutic is often long and arduous. Understanding the precise mechanisms by which estrogen-related receptors function in muscle cells, and how they interact with other metabolic pathways, opens up new and exciting opportunities for therapeutic development. The next phases of research will undoubtedly involve a deeper exploration into the specific functions and intricate regulatory networks of both alpha- and gamma-type receptors. This detailed understanding may unveil additional potential therapeutic targets within the ERR family or related pathways, offering multiple avenues for intervention.
The development of a drug to selectively activate ERRs will require rigorous preclinical testing, followed by multiple phases of human clinical trials to ensure both efficacy and safety. This process could take many years, but the clarity of ERRα’s role as a direct gene binder makes it a more tractable target than many other complex regulatory proteins. The scientific community, patient advocacy groups, and pharmaceutical industry will be closely watching these developments, recognizing the immense potential to address some of the most challenging and widespread health issues of our time.
This monumental work was the result of a collaborative effort, with other key authors including 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. Contributions also came from Tae Gyu Oh, affiliated with both Salk and the University of Oklahoma, and Christopher Liddle from the University of Sydney, Australia. The research received substantial financial backing from prestigious institutions, 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. These substantial investments underscore the recognized importance and potential impact of this line of metabolic research.
