LA JOLLA, CA – May 12, 2025 – A groundbreaking study from the Salk Institute, published today in the Proceedings of the National Academy of Sciences, has unveiled a previously underappreciated pathway that could revolutionize the treatment of metabolic disorders and age-related muscle fatigue. Scientists have discovered that a group of proteins known as estrogen-related receptors (ERRs) play an indispensable role in maintaining and enhancing cellular energy metabolism, particularly within muscle cells. This pivotal finding suggests that targeting these receptors could be a powerful new strategy to repair dysfunctional mitochondria, the cellular powerhouses that are vital for our energy and movement.
The implications of this research are profound. With mitochondrial dysfunction affecting millions globally, from those born with genetic conditions to individuals experiencing age-related decline or diseases such as cancer, multiple sclerosis (MS), heart disease, and dementia, the prospect of a new therapeutic avenue offers a beacon of hope. The study specifically highlights the potential to develop drugs that boost ERR activity, thereby restoring energy supplies and combating muscle weakness and fatigue, particularly in conditions like muscular dystrophy.
The Foundation of Life: Mitochondria and Metabolic Dysfunction
At the heart of every cell in our body are tiny, bean-shaped organelles called mitochondria. Often referred to as the "powerhouses of the cell," mitochondria are responsible for converting the food we eat into adenosine triphosphate (ATP), the usable energy currency that fuels virtually every biological process. This cellular-level metabolism is especially critical in muscle cells, which demand vast amounts of energy to power movement, from the subtlest twitch to strenuous exercise.
However, this intricate energy production system is vulnerable to disruption. It is estimated that 1 in 5,000 people are born with dysfunctional mitochondria, leading to a spectrum of severe metabolic disorders. Beyond these congenital conditions, countless others develop metabolic dysfunction later in life. This can be a consequence of the natural aging process, where mitochondrial efficiency often declines, or it can be intricately linked to a host of chronic diseases. Conditions like certain cancers, multiple sclerosis, various forms of heart disease, and even neurodegenerative disorders such as dementia often feature compromised mitochondrial function as a contributing factor to their pathology and the pervasive fatigue experienced by patients.
Despite the widespread impact of mitochondrial dysfunction, effective treatments remain elusive. The complexity of cellular metabolism and the ubiquitous nature of mitochondria across all body systems have made targeted therapies challenging to develop. This pressing need for innovative solutions has driven researchers worldwide to explore novel biological pathways that could offer a breakthrough.
A Decades-Long Quest: Unraveling the Role of Nuclear Hormone Receptors
The recent Salk Institute findings are the culmination of decades of pioneering research, spearheaded by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Evans’s distinguished career began to illuminate the intricate world of gene regulation in the 1980s with his landmark discovery of a family of proteins he named "nuclear hormone receptors." These remarkable receptors act as molecular switches: they bind to specific hormones and, in turn, attach themselves to our DNA, controlling which genes get turned "on" or "off." This fundamental mechanism dictates a vast array of physiological processes, from development and metabolism to reproduction and immunity.
Among the many branches of this expansive family of nuclear hormone receptors are the estrogen-related receptors (ERRs). While their name suggests a connection to classic estrogen receptors, Evans notes a crucial distinction: "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood." It was Evans’s lab that first discovered estrogen-related receptors in 1988, and they were among the first to recognize their potential role in energy metabolism.
This initial insight laid the groundwork for further investigation. Scientists observed that ERRs are particularly abundant in parts of the body that have high energy demands, such as the heart and the brain – organs that are critically dependent on robust mitochondrial function. This observation naturally led Evans’s team to hypothesize that ERRs might also play a significant role in regulating metabolism in another high-energy organ: skeletal muscle.
The Current Breakthrough: ERRs as Indispensable Drivers of Muscle Energy
Muscles are notoriously energy-intensive, especially during physical activity. Exercise is one of the most potent natural signals for muscle cells to initiate mitochondrial biogenesis – the process by which a cell increases the number of its mitochondria to produce more fuel. This adaptive response allows muscles to meet increased energy demands and improve endurance. However, for individuals suffering from muscular and metabolic disorders, exercise is often an insurmountable challenge. This reality has spurred scientists to search for alternative, pharmacological ways to stimulate mitochondrial biogenesis.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains Weiwei Fan, the first author of the study and a staff scientist in Evans’s 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."
To systematically investigate the role of ERRs in muscle cell metabolism, Fan and his colleagues embarked on a series of meticulous experiments. They employed 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 examining the resulting effects on muscle function and mitochondrial health, the researchers aimed to pinpoint the specific contributions of each receptor type.
Their initial findings were illuminating. While ERRα was found to be the most abundant type of receptor in muscle tissue, its isolated deletion had surprisingly mild impacts under normal, resting conditions. This suggested a degree of redundancy or compensatory mechanisms at play. Further investigation revealed that the ERRγ receptor, despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, was capable of compensating for the loss of ERRα under these baseline conditions.
The critical insight emerged when the researchers deleted both the alpha and gamma types of ERRs. This combined loss led to severe impairments in muscle mitochondrial activity, significantly altering their shape and reducing their overall size. This indicated that while ERRα is numerically dominant, ERRγ plays a crucial, complementary role in maintaining fundamental mitochondrial health.
The presence of such an overwhelming excess of the alpha-type estrogen-related receptor (ERRα) in muscle prompted the team to hypothesize that its primary role might be to help muscles adapt and grow in response to exercise. To test this, the researchers had their genetically modified mice engage in exercise on mechanical wheels. This regimen was designed to trigger mitochondrial biogenesis, allowing the scientists to precisely assess whether ERRα was indeed involved in this exercise-induced adaptive process. The results were striking: losing ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This established ERRα as an indispensable component of the muscle’s adaptive response to physical activity.
Prior research had already identified another protein, PGC1α, as the "master regulator" of mitochondria throughout the body, known for driving exercise-induced mitochondrial growth. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes to turn them on or off. Instead, it relies on partner proteins to execute its functions, an indirect action that makes it a more difficult target for pharmacological intervention.
The Salk team’s breakthrough came when they examined muscle cells after exercise and discovered the crucial partnership: PGC1α was actively collaborating with ERRα to drive mitochondrial biogenesis. But unlike PGC1α, ERRα possesses the ability to bind directly to mitochondrial energetic genes and activate them. This direct transcriptional control makes ERRα an exceptionally promising target for improving muscle’s mitochondrial performance through drug-based therapies.
Official Responses and Expert Insights
The discovery has generated considerable excitement within the scientific community, particularly from the lead researchers who have dedicated their careers to understanding these fundamental biological processes.
Professor Ronald Evans, whose lab first identified ERRs decades ago, expressed the significance of this latest finding: "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood. Our lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism. 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." Evans’s long-standing commitment to unraveling the complexities of nuclear hormone receptors underscores the depth and rigor behind this discovery, highlighting a full-circle moment for his pioneering research.
Weiwei Fan, the study’s first author, emphasized the broader implications of their work: "Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need. 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." Fan further elaborated on the systemic benefits: "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." His insights underscore the potential for a cascading positive effect on overall health.
The Salk Institute, a global leader in biological research, views this discovery as a testament to its mission to explore fundamental biology and translate it into practical solutions for human health. A representative from the institute noted, "This research exemplifies the Salk Institute’s unwavering commitment to unraveling the most complex biological puzzles. By identifying ERRs as direct regulators of mitochondrial biogenesis, Professor Evans and Dr. Fan have opened a critical new door for therapeutic development, promising to significantly improve the quality of life for countless individuals grappling with metabolic and muscle-related disorders."
Profound Implications and Future Directions
The identification of estrogen-related receptors, particularly ERRα, as direct and indispensable drivers of mitochondrial growth and activity in muscle cells marks a significant advancement in metabolic research. This discovery carries profound implications for medicine and public health, offering a tantalizing new target for drug development.
Therapeutic Potential: The most immediate and exciting implication is the potential to develop novel pharmacological interventions. For patients with debilitating metabolic disorders like muscular dystrophy, where progressive muscle weakness and fatigue severely impact quality of life, a drug that could pharmacologically stimulate mitochondrial biogenesis would be transformative. Beyond rare genetic conditions, such a therapeutic could also address the widespread muscle fatigue associated with aging, chronic diseases such as cancer, multiple sclerosis, and various forms of heart disease, and even the cognitive decline seen in dementia, where brain energy metabolism is often compromised. By bypassing the need for physical exercise – which is often impossible for these patient populations – an ERR-activating drug could offer a vital pathway to energy restoration.
Broader Health Benefits: The ripple effects of improved mitochondrial function extend far beyond muscle tissue. As Fan highlighted, "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." The brain, being the most energy-demanding organ, could benefit from enhanced mitochondrial health, potentially offering new strategies to combat neurodegenerative diseases or age-related cognitive decline. Similarly, the heart, a muscle that works tirelessly throughout life, is highly susceptible to mitochondrial dysfunction in conditions like heart failure. Targeting ERRs could provide a novel approach to bolstering cardiac function and resilience.
Scientific Paradigm Shift: This research also refines our understanding of how cellular energy is regulated and how nuclear hormone receptors operate. By establishing ERRα as a direct transcriptional activator, it distinguishes it from more indirect regulators like PGC1α, making it a more accessible and attractive target for drug design. This provides a clearer roadmap for future investigations into metabolic pathways.
Future Research Directions: The Salk team’s findings are not an end but a new beginning. Future research will undoubtedly delve deeper into the nuanced functions and regulatory mechanisms of both alpha- and gamma-type estrogen-related receptors. Understanding how these different ERR subtypes interact and compensate for each other under various physiological and pathological conditions will be crucial. This deeper understanding may lead to the identification of other potential therapeutic targets within the ERR pathway or related regulatory networks. Scientists will also focus on developing and testing specific ERR-activating compounds, rigorously evaluating their efficacy, safety, and potential side effects in preclinical and, eventually, clinical trials.
Economic and Societal Impact: The development of effective treatments for metabolic dysfunction could have a substantial societal impact. By improving the physical capabilities and overall energy levels of affected individuals, such therapies could enhance quality of life, reduce dependency on caregivers, and potentially alleviate a significant portion of the healthcare burden associated with chronic diseases and aging.
The work 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 comprehensive nature of this research, from its historical roots in basic discovery to its clear translational potential, positions estrogen-related receptors as a frontier in the battle against metabolic decline. As the Salk Institute continues its relentless pursuit of scientific excellence, the prospect of restoring vital energy supplies and combating debilitating fatigue moves closer to reality, promising a healthier, more energetic future for millions.
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