By Billy Candra 
LA JOLLA, CA – May 12, 2025 – A pivotal study from the Salk Institute has unveiled a groundbreaking mechanism involving estrogen-related receptors (ERRs) that could revolutionize the treatment of metabolic disorders and associated muscle fatigue. Published today in the prestigious Proceedings of the National Academy of Sciences, the research identifies ERRs as indispensable drivers of mitochondrial growth and activity within muscle cells, offering a promising new therapeutic target for a spectrum of debilitating conditions. This discovery, building on decades of foundational research, provides a direct pharmacological avenue to enhance cellular energy production, a process critical for overall health and particularly vital for muscle function.
The Ubiquitous Challenge of Mitochondrial Dysfunction
At the very core of our biological existence, tiny, bean-shaped organelles known as mitochondria function as the cellular powerhouses, converting the food we consume into adenosine triphosphate (ATP), the usable energy currency of the body. This intricate process of cellular metabolism is paramount in all tissues, but it holds exceptional importance in muscle cells, which demand substantial energy reserves to facilitate movement, from simple daily tasks to intense physical exertion.
However, this finely tuned system is susceptible to dysfunction. Approximately 1 in 5,000 individuals are born with congenital mitochondrial disorders, leading to severe, often life-limiting health challenges. Beyond these genetic predispositions, a much larger segment of the population develops metabolic dysfunction later in life. This acquired impairment is frequently linked to the natural processes of aging and is a common characteristic of numerous chronic diseases, including various forms of cancer, multiple sclerosis (MS), congestive heart failure, and neurodegenerative conditions like Alzheimer’s and Parkinson’s disease. According to the Centers for Disease Control and Prevention (CDC), metabolic syndrome, a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels, affects more than one-third of U.S. adults and significantly increases the risk for heart disease, stroke, and type 2 diabetes. The global prevalence of these metabolic challenges underscores the urgent need for effective therapeutic interventions.
The symptoms of mitochondrial dysfunction are diverse and debilitating, ranging from profound muscle weakness and chronic fatigue to neurological impairments and organ system failure. Current treatment options are largely supportive, focusing on managing symptoms rather than addressing the root cause of energy deficits. This therapeutic void has spurred relentless research into novel strategies to restore mitochondrial health and function, making the Salk Institute’s latest findings particularly impactful.
A Decades-Long Quest: Unearthing the Power of Nuclear Hormone Receptors
The current breakthrough is not an isolated discovery but rather the culmination of a distinguished research lineage spearheaded by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Evans’ pioneering work in the 1980s led to the landmark identification of a family of proteins he aptly named "nuclear hormone receptors." These extraordinary proteins act as molecular switches, binding to specific hormones and then attaching themselves directly to our DNA, where they exert profound control over gene expression, turning specific genes "on" or "off." This fundamental discovery reshaped our understanding of how hormones regulate virtually every physiological process in the body.
Among the various branches of this expansive family, the estrogen-related receptors (ERRs) were first discovered by Evans’ lab in 1988. From early on, researchers recognized their significant, albeit less understood, role in energy metabolism. Unlike classic estrogen receptors, ERRs do not bind to estrogen, but their structural similarity led to their nomenclature. Early investigations hinted at their prevalence in organs with high energy demands, such as the heart and brain, suggesting their integral role in maintaining robust metabolic activity in these critical systems. This early insight served as the intellectual bedrock for the current study, inspiring Evans’ team to delve deeper into the specific regulatory functions of ERRs, particularly within skeletal muscle – another organ characterized by its voracious appetite for fuel.
The Salk Study: Unraveling ERRs’ Indispensable Role in Muscle Metabolism
The impetus for the Salk team’s focused investigation into muscle metabolism stemmed from a well-established physiological principle: exercise is one of the most potent natural signals for muscle tissue to trigger mitochondrial biogenesis. This process involves the creation of new mitochondria and the enhancement of existing ones, effectively increasing the cell’s capacity to produce more energy. However, for individuals grappling with muscular dystrophies, chronic fatigue syndrome, or other metabolic and neuromuscular disorders, strenuous exercise is often an impossible or counterproductive endeavor. This stark reality highlighted the critical need for alternative, pharmacologically inducible methods to stimulate mitochondrial biogenesis.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explained Weiwei Fan, the first author of the study and 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 foundational question guided the research team’s meticulous experimental design.
To definitively ascertain the role of ERRs in muscle cell metabolism, Fan and his colleagues conducted a series of sophisticated experiments involving genetically modified mice. They systematically deleted three distinct forms of these receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of these mice. The subsequent analysis of these models provided crucial insights into the hierarchical and compensatory roles of these ERR subtypes.
Their initial observations revealed that ERRα was by far the most abundant type of receptor in muscle tissue. Interestingly, the isolated loss of ERRα initially showed only mild impacts on muscle tissue function under normal, resting conditions. This seemingly minor effect was explained by a compensatory mechanism: the researchers discovered that ERRγ, despite constituting only about 4% of the total ERR population, was capable of stepping in and largely compensating for the absence of ERRα under these baseline circumstances. However, the scenario dramatically changed when both ERRα and ERRγ were simultaneously deleted. This dual deletion led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size, and drastically reducing their energetic output. This finding underscored the critical, albeit partially redundant, roles of these two receptor types in maintaining baseline mitochondrial health.
The team then hypothesized that the significant excess of ERRα might play a specialized role in situations of heightened metabolic demand, such as during exercise. To test this, they subjected their genetically modified mice to exercise regimens on mechanical wheels. This exercise protocol reliably triggers mitochondrial biogenesis in healthy muscles, providing an ideal model to assess ERRα’s specific involvement. The results were striking: the loss of ERRα alone was sufficient to completely block the exercise-induced mitochondrial biogenesis. This pivotal finding conclusively demonstrated that ERRα is not merely abundant but is an indispensable mediator of the muscle’s adaptive response to physical activity.
The PGC1α Connection and Therapeutic Advantage
Previous research had firmly established that exercise-induced mitochondrial growth was largely driven by another protein known as PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α is widely recognized as a "master regulator" of mitochondria throughout the body, orchestrating the complex processes required for mitochondrial biogenesis and function. However, PGC1α presents a significant challenge for therapeutic drug development: unlike nuclear hormone receptors such as ERRs, PGC1α cannot directly bind to genes. Instead, it operates 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 notoriously difficult target for small-molecule drugs, which typically aim to directly interact with specific proteins to modulate their activity.
This is where the Salk Institute’s latest discovery offers a profound therapeutic advantage. When Evans’ lab meticulously examined the muscle cells after exercise, they found the crucial link: PGC1α was indeed partnering with ERRα to drive mitochondrial biogenesis. But critically, and unlike PGC1α, ERRα can directly bind to the mitochondrial energetic genes themselves and effectively turn them "on." This direct gene-binding capability positions ERRα as a far more accessible and potent target for pharmacological intervention. Developing a drug that directly activates ERRα could bypass the complexities of indirectly modulating PGC1α, offering a straightforward path to improving muscle’s mitochondrial performance and energy supply.
Broad Implications and Future Horizons
The ramifications of these findings extend far beyond the realm of muscle function. As Weiwei Fan eloquently states, "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." Given that ERRs are found in other high-energy organs such as the brain and heart, improving mitochondrial function and energy metabolism through ERR activation could potentially strengthen a multitude of different organ systems. This holds immense promise for addressing conditions like chronic heart failure, where cardiac muscle energy metabolism is often compromised, or neurodegenerative diseases, where neuronal energy deficits are a key pathological feature.
The discovery of ERRs as direct, targetable regulators of mitochondrial biogenesis represents a significant leap forward in the quest to combat metabolic dysfunction. For the medical community, this research opens up a new frontier for developing a novel class of therapeutics that could dramatically improve the quality of life for millions of patients. Patient advocacy groups, such as the Muscular Dystrophy Association, the Multiple Sclerosis Society, and organizations dedicated to combating chronic fatigue syndrome, will undoubtedly welcome this breakthrough with immense hope, recognizing the potential for therapies that could address the fundamental energy deficits underlying these debilitating conditions. The pharmaceutical sector, too, will observe this development with keen interest, as it presents a clear and validated molecular target for drug discovery and development in a market segment with vast unmet medical needs.
Understanding the intricate mechanisms by which estrogen-related receptors function in muscle cells creates unprecedented opportunities to develop targeted interventions for all parts of the body affected by mitochondrial dysfunction. While the immediate focus is on muscle weakness and fatigue, the broader implications for age-related decline, metabolic syndrome, and even general well-being are substantial. Future research will undoubtedly continue to explore the precise function and regulation of both alpha- and gamma-type receptors, potentially uncovering additional nuances and leading to the identification of other synergistic therapeutic targets.
This monumental work was the result of a collaborative effort involving a dedicated team of researchers. Other authors on 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. The extensive and impactful nature of this research was made possible through generous support from a consortium of funders, 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.
The Salk Institute, renowned for its pioneering contributions to biomedical science, continues to push the boundaries of knowledge. This latest discovery underscores its commitment to unraveling fundamental biological processes and translating these insights into tangible advancements for human health. As the scientific community looks toward the clinical translation of these findings, the promise of new, effective treatments for metabolic disorders and muscle fatigue appears brighter than ever.
