By Billy Candra 
A groundbreaking study from the Salk Institute, published in Proceedings of the National Academy of Sciences on May 12, 2025, has identified a family of proteins known as estrogen-related receptors (ERRs) as a crucial link in repairing energy metabolism and combating muscle fatigue. This discovery illuminates a novel therapeutic pathway for a wide spectrum of conditions marked by metabolic dysfunction, ranging from inherited mitochondrial disorders to age-related decline and chronic diseases like multiple sclerosis, heart disease, and dementia. The findings suggest that targeting these receptors could offer a powerful strategy to restore vital energy supplies in affected individuals.
The Ubiquitous Role of Mitochondria in Health and Disease
At the very core of cellular life, tiny, bean-shaped organelles called mitochondria serve as the indispensable "powerhouses" of the cell. They are responsible for converting the food we consume into adenosine triphosphate (ATP), the primary energy currency that fuels nearly every biological process. This intricate cellular-level metabolism is particularly vital in muscle cells, which demand an immense amount of energy to facilitate movement, maintain posture, and perform strenuous activities. Without efficiently functioning mitochondria, muscle cells struggle, leading to debilitating weakness and profound fatigue.
Mitochondrial dysfunction is not a rare anomaly. It affects approximately 1 in 5,000 individuals from birth, manifesting as primary mitochondrial diseases that can impact multiple organ systems. Beyond these genetic predispositions, a significantly larger population develops metabolic dysfunction later in life. This acquired form is frequently associated with the natural aging process, where mitochondrial efficiency often declines, contributing to sarcopenia (age-related muscle loss) and general frailty. Furthermore, numerous pervasive diseases, including various cancers, neurodegenerative conditions like Alzheimer’s and Parkinson’s, cardiovascular diseases, and autoimmune disorders such as multiple sclerosis (MS), have been increasingly linked to impaired mitochondrial function. The sheer prevalence and diverse manifestations of these conditions underscore the urgent need for effective therapeutic interventions that address the root cause of energy deficits.
Unraveling the Mystery of Estrogen-Related Receptors
Despite the critical role of mitochondria, treating their dysfunction has historically proven challenging. Current approaches often involve managing symptoms or providing supportive care, with few targeted therapies available. It is against this backdrop that the Salk Institute’s latest research emerges as a beacon of hope, spotlighting estrogen-related receptors as a promising and previously underestimated therapeutic target.
The scientific journey to understand ERRs is intertwined with the pioneering work of Dr. Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, and the senior author of the new study. In the 1980s, Dr. Evans led the landmark discovery of a vast family of proteins he termed "nuclear hormone receptors." These receptors are unique in their ability to directly interact with DNA, acting as molecular switches that control the expression of specific genes. They are activated by various hormones, allowing the body to respond to environmental cues and maintain physiological balance.
Estrogen-related receptors were identified by Evans’ lab in 1988 as a distinct branch of this nuclear hormone receptor family. Initially, their precise function was less understood compared to their classic estrogen receptor counterparts, which are well-known for their roles in reproductive health and cancer. However, early investigations by Evans’ team hinted at their involvement in energy metabolism, noting their abundance in metabolically active tissues such as the heart and brain—organs that constantly require significant fuel to operate. This observation fueled the current research, inspiring Dr. Evans’ team to delve deeper into the potential role of ERRs in regulating metabolism within another high-energy organ: skeletal muscle.
Exercise as a Molecular Trigger: The Quest for Mimetics
Skeletal muscles are metabolic titans, especially during physical activity. Exercise is one of the most potent natural signals for triggering mitochondrial biogenesis—a fundamental cellular process where a cell increases the number and improves the quality of its mitochondria to meet higher energy demands. This adaptive response is crucial for improving endurance, strength, and overall metabolic health. However, for individuals grappling with muscular and metabolic disorders, or those weakened by age or chronic illness, engaging in sufficient exercise to stimulate this vital process is often impossible. This physiological barrier has long driven scientists to search for "exercise mimetics"—pharmacological or nutritional interventions that can induce the benefits of exercise without the physical exertion.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains Weiwei Fan, a staff scientist in Dr. Evans’ lab and the first author of the study. "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 their investigation into the precise mechanisms by which muscles adapt to energy demands.
Deciphering ERR’s Role: Insights from Genetic Deletion
To meticulously investigate the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues employed a sophisticated genetic approach. They systematically deleted three different forms of ERRs—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of laboratory mice. This allowed them to observe the resulting physiological and metabolic consequences in a controlled environment.
Their initial observations revealed a complex interplay among the ERR subtypes. ERRα was found to be the most abundant receptor in muscle tissue. Surprisingly, the loss of ERRα alone had only mild impacts on muscle function under normal, resting conditions. This seemingly counterintuitive finding led them to further explore the compensatory mechanisms at play. They discovered that ERRγ, despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, possessed a remarkable capacity to compensate for the absence of ERRα under typical physiological circumstances. However, the scenario changed dramatically when both ERRα and ERRγ were deleted. The combined loss of these two receptors led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size and compromising their ability to produce energy efficiently.
This intricate balance suggested that while ERRγ could serve as a backup, ERRα might have a specialized role that becomes paramount under specific conditions. The team hypothesized that the substantial abundance of ERRα was not redundant but rather essential for muscles to adapt and grow in response to elevated energy demands, particularly during exercise.
ERRα: The Indispensable Driver of Exercise Adaptation
To test this hypothesis, the researchers introduced an exercise regimen for their mice, utilizing mechanical wheels. This controlled exercise protocol reliably triggered mitochondrial biogenesis in the muscle cells of normal mice, providing a clear model to assess ERRα’s involvement. The results were striking: mice lacking ERRα alone were completely unable to initiate exercise-induced mitochondrial biogenesis. This profound finding established ERRα as an indispensable driver of the muscle’s adaptive response to physical exertion, explaining its high abundance and critical function.
The findings also shed light on the long-understood role of another key protein: PGC1α (peroxisome proliferator-activated receptor-gamma coactivator 1-alpha). PGC1α has been celebrated as the "master regulator" of mitochondria throughout the body, known to orchestrate mitochondrial growth and function. However, PGC1α itself cannot directly bind to DNA and activate genes. Instead, it relies on partner proteins to execute its regulatory functions. This indirect mode of action makes PGC1α a more challenging target for therapeutic drug development, as modulating its activity without affecting its numerous other partners can be difficult.
The Salk team’s breakthrough revealed the crucial partnership between these two regulatory powerhouses. When Dr. Evans’ lab examined muscle cells after exercise, they observed that PGC1α was physically interacting with ERRα to drive the process of mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the ability to bind directly to mitochondrial energetic genes and turn them "on." This direct gene-activating capability positions ERRα as an exceptionally promising and "druggable" target for pharmacological intervention aimed at improving mitochondrial performance and combating muscle weakness.
Broader Implications and Future Therapeutic Avenues
The discovery that activating estrogen-related receptors, particularly ERRα, can directly enhance mitochondrial function and energy metabolism in muscles carries profound implications extending far beyond just muscle repair. "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," states Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
This systemic impact is a critical aspect of the research. Conditions such as heart failure, where the heart muscle struggles to pump blood efficiently, and neurodegenerative diseases like Alzheimer’s, which are increasingly linked to impaired brain energy metabolism, could potentially benefit from therapies that boost ERR activity. The study opens new avenues for developing small molecule drugs that specifically activate ERRs, thereby mimicking the beneficial effects of exercise at a molecular level.
For patients suffering from conditions like muscular dystrophy, a group of genetic diseases characterized by progressive muscle weakness and degeneration, this research offers a tangible new direction. Current treatments for muscular dystrophy often focus on symptom management, but a therapy that directly addresses mitochondrial health and energy production could fundamentally alter the disease course. Similarly, individuals experiencing chronic fatigue associated with long COVID, cancer treatments, or aging could find significant relief from such interventions.
The Path Forward: From Bench to Bedside
The journey from a laboratory discovery to a clinical drug is arduous, but the Salk Institute’s findings lay a strong foundation. Understanding the precise mechanisms by which ERRs function in muscle cells creates unprecedented opportunities to develop targeted therapies. Future research will undoubtedly focus on several key areas:
- Drug Discovery: Identifying and optimizing small molecules that can selectively activate ERRα and ERRγ, ensuring specificity and minimizing potential off-target effects.
- Preclinical Testing: Rigorous testing of these potential drug candidates in animal models of various metabolic disorders to assess efficacy, safety, and optimal dosing.
- Human Trials: If preclinical studies are successful, moving to human clinical trials to evaluate the drugs’ effectiveness in patients.
- Further Characterization: Continuing to explore the nuanced functions and regulatory networks of both alpha- and gamma-type ERRs, which may unveil additional therapeutic targets or refine existing strategies.
The scientific community is likely to greet these findings with considerable enthusiasm. Dr. Evans’ long-standing contributions to the field of nuclear hormone receptors have repeatedly opened new frontiers in medicine, and this latest work is no exception. Patient advocacy groups, such as the Muscular Dystrophy Association, the National Multiple Sclerosis Society, and organizations dedicated to combating age-related diseases, are anticipated to welcome this research as a significant step towards improving the quality of life for millions affected by debilitating energy deficits. The prospect of a "druggable" target for mitochondrial dysfunction represents a paradigm shift, moving beyond symptomatic treatment to addressing the fundamental energetic health of our cells.
This monumental effort was a collaborative endeavor, with significant contributions from other authors including 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 work received generous support from a consortium of institutions and foundations, including the National Institutes of Health, the Department of the Navy, the Larry L. Hillblom Foundation, Inc., the Wu Tsai Human Performance Alliance, the Henry L. Guenther Foundation, and the Waitt Foundation, underscoring the broad recognition of the research’s potential impact on human health.
