LA JOLLA, CA – May 12, 2025 – In a discovery poised to revolutionize the treatment of metabolic disorders and age-related muscle decline, scientists at the Salk Institute for Biological Studies have identified a group of proteins, known as estrogen-related receptors (ERRs), as critical drivers of energy metabolism and muscle function. A groundbreaking study, published today in the prestigious Proceedings of the National Academy of Sciences, reveals that these receptors are indispensable for mitochondrial growth and activity within muscle cells, presenting a highly promising new therapeutic target for a spectrum of debilitating conditions ranging from muscular dystrophy to the metabolic challenges associated with aging, cancer, multiple sclerosis (MS), heart disease, and dementia.
The research illuminates a previously underappreciated pathway by which our bodies generate and utilize energy, particularly in the high-demand environment of skeletal muscle. By demonstrating that ERRs can significantly boost the number and efficiency of mitochondria – the cellular powerhouses that convert food into usable energy – the Salk team has opened a novel avenue for restoring vitality and combating the pervasive problem of muscle weakness and fatigue.
The Looming Challenge of Mitochondrial Dysfunction
At the core of cellular life lies metabolism, a complex symphony of biochemical reactions that sustain every function, from brain activity to muscle contraction. Crucial to this process are mitochondria, the tiny, bean-shaped organelles often dubbed the "power plants" of the cell. They tirelessly convert the nutrients we consume into adenosine triphosphate (ATP), the universal energy currency of life. This intricate cellular-level metabolism is especially vital in muscle cells, which demand vast amounts of fuel to power our every movement, from a gentle stretch to an intense sprint.
However, this finely tuned system is vulnerable. Mitochondrial dysfunction, a condition where these cellular powerhouses fail to operate efficiently, affects a significant portion of the population. It is estimated that 1 in 5,000 individuals are born with congenital mitochondrial disorders, leading to severe and often debilitating symptoms impacting various organ systems. Beyond these inherited conditions, countless others develop metabolic dysfunction later in life, a silent epidemic often associated with the natural process of aging. As we grow older, mitochondrial efficiency can decline, contributing to sarcopenia (age-related muscle loss), decreased energy levels, and a heightened susceptibility to chronic diseases. Moreover, a growing body of evidence links mitochondrial impairment to a wide array of devastating diseases, including certain cancers, the neurodegenerative hallmarks of multiple sclerosis and dementia, and the cardiovascular stresses of heart disease.
Despite its widespread impact, mitochondrial dysfunction has historically proven difficult to treat. Current therapeutic strategies are often limited to symptomatic relief or supportive care, with few options addressing the root cause of energy deficits. This lack of effective interventions has spurred an urgent global search for novel therapeutic targets that can restore metabolic health and improve the quality of life for millions.
A Legacy of Discovery: Unveiling Nuclear Hormone Receptors
The recent findings from the Salk Institute are not an isolated breakthrough but rather the culmination of decades of pioneering research led by Professor Ronald Evans, a towering figure in molecular biology and the March of Dimes Chair in Molecular and Developmental Biology at Salk. His laboratory has a rich history of unraveling the intricate mechanisms by which our bodies regulate gene expression and metabolism.
The story begins in the 1980s, a transformative era in molecular biology, when Evans spearheaded the landmark discovery of a groundbreaking family of proteins he aptly named "nuclear hormone receptors." These extraordinary receptors act as molecular switches, residing within the nucleus of our cells. Their unique ability lies in their capacity to bind to specific hormones – such as steroids, thyroid hormones, and vitamins – and subsequently attach themselves directly to our DNA. Upon binding, they act as powerful transcription factors, controlling which genes get turned "on" or "off," thereby orchestrating a vast array of physiological processes, including development, reproduction, and metabolism. This seminal work fundamentally changed our understanding of how hormones exert their profound effects on the body.
Among the numerous branches of this expansive nuclear hormone receptor family, Evans’ lab specifically identified the estrogen-related receptors (ERRs) in 1988. Even then, the team recognized their potential significance, being among the first to acknowledge their nascent role in energy metabolism. Unlike classic estrogen receptors, which respond directly to the female hormone estrogen, ERRs are "orphan receptors" – meaning their activating ligand, if any, was initially unknown, and they do not directly bind estrogen. Despite this, their structural resemblance to classic estrogen receptors led to their nomenclature. What became increasingly clear was their ubiquitous presence in parts of the body characterized by high energy demands, such as the heart, brain, and, notably, skeletal muscle. This intriguing distribution naturally inspired Evans’ team to delve deeper into their potential role in regulating metabolism within these high-energy organs, setting the stage for the current groundbreaking study.
The Research Journey: From Hypothesis to Indispensable Drivers
Muscles, by their very nature, are energy-hungry tissues. This demand intensifies dramatically during physical activity. In fact, exercise is one of the most potent natural signals for muscle cells to trigger a vital process known as mitochondrial biogenesis. During biogenesis, a cell actively increases both the number and mass of its mitochondria, effectively expanding its "energy factory" capacity to meet heightened fuel requirements. However, this natural adaptive mechanism presents a cruel paradox for individuals suffering from muscular and metabolic disorders. For these patients, the very act of exercising is often difficult, if not impossible, due to severe weakness, pain, or fatigue. This challenging reality has driven scientists to seek alternative, pharmacological avenues to stimulate mitochondrial biogenesis, mimicking the beneficial effects 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, the first author of the study and a staff scientist in Evans’ lab. "This got us thinking – if we could understand precisely how exercise induces mitochondrial biogenesis, we might be able to target those same underlying mechanisms pharmacologically. This would allow us to trigger this crucial process in people who are too weak to exercise, offering them a chance to restore their energy and muscle function."
To rigorously test their hypothesis regarding the role of estrogen-related receptors in muscle cell metabolism, Fan and his colleagues embarked on a meticulous experimental journey. They employed advanced genetic techniques to selectively delete three different forms, or isoforms, of these receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – specifically within the muscle tissues of laboratory mice. This precise genetic manipulation allowed the researchers to observe the resulting physiological and molecular effects on mitochondrial activity, shape, and size, thereby pinpointing the specific contributions of each ERR isoform.
Their initial observations revealed a complex interplay among the ERR isoforms. They found that while ERRα was the most abundantly expressed type of receptor in muscle tissue, its isolated loss had only mild impacts on overall muscle function under normal, resting conditions. This intriguing resilience suggested a compensatory mechanism at play. Indeed, the researchers discovered that ERRγ, despite making up only a small fraction (approximately 4%) of the total estrogen-related receptors, possessed a remarkable ability to compensate for the absence of ERRα under these baseline conditions. This suggested a degree of functional redundancy or a backup system.
However, the picture changed dramatically when both the alpha and gamma types of ERRs were simultaneously deleted. This dual deletion led to severe and unmistakable impairments in muscle mitochondrial activity. The mitochondria within these muscle cells exhibited abnormal shapes, reduced sizes, and significantly diminished energy output. This critical finding underscored the collective importance of ERRs, particularly ERRα and ERRγ, in maintaining baseline mitochondrial health and function.
The researchers then turned their attention to the question of ERRα’s seemingly superfluous abundance. If ERRγ could compensate, why was ERRα so prevalent? Hypothesizing that ERRα’s true indispensable role might emerge under conditions of metabolic stress or heightened energy demand, the team designed an elegant experiment: they had their genetically modified mice engage in voluntary exercise on mechanical wheels. This exercise regimen was specifically chosen because it is a well-established trigger for mitochondrial biogenesis, providing the ideal context to assess whether ERRα was indeed involved in this crucial adaptive process.
The results were unequivocal and striking. The experiment definitively revealed that losing ERRα alone could entirely block exercise-induced mitochondrial biogenesis. Despite the physical exertion, the muscles of mice lacking ERRα were unable to increase their mitochondrial numbers or enhance their energy-producing capacity. This finding cemented ERRα’s status as an "indispensable driver" of the muscle’s adaptive response to exercise, a role that goes far beyond its baseline contribution.
Prior scientific investigations had previously established that exercise-induced mitochondrial growth was primarily driven by another well-known protein called PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α has long been celebrated as the "master regulator" of mitochondria throughout the body due to its profound influence on mitochondrial biogenesis and metabolic adaptation. 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 operates indirectly, requiring partner proteins to carry out its genetic instructions. This indirect mode of action makes PGC1α a considerably more difficult target for pharmacological intervention, as developing drugs to modulate coactivator activity is inherently complex.
This is where the Salk team’s new discovery truly shines. When Evans’ lab meticulously examined the muscle cells after exercise, they found a critical partnership at play: PGC1α was indeed working in concert with ERRα to drive mitochondrial biogenesis. Crucially, however, unlike PGC1α, ERRα possesses the unique and highly advantageous ability to bind directly to mitochondrial energetic genes. This direct binding allows ERRα to turn these genes "on," directly orchestrating the production of new mitochondria and enhancing their performance. This direct action makes ERRα an exceptionally promising and "druggable" target for improving muscle’s mitochondrial performance and, by extension, overall metabolic health.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," says senior author Ronald Evans. "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."
Broader Implications and Official Responses
The implications of this discovery extend far beyond the realm of skeletal muscle. The Salk Institute’s findings represent a significant leap forward in our understanding of metabolic regulation and offer a beacon of hope for a wide spectrum of health challenges. The ability to pharmacologically activate estrogen-related receptors could usher in a new era of therapeutic interventions for diseases characterized by energy deficits and muscle wasting.
For patients suffering from muscular dystrophies, such as Duchenne muscular dystrophy, where progressive muscle degeneration leads to severe weakness and loss of function, a drug that can enhance mitochondrial function and muscle energy supply could fundamentally alter the disease trajectory, improving muscle integrity and slowing progression. Similarly, for individuals battling the chronic fatigue and muscle weakness associated with multiple sclerosis (MS) or the cachexia (wasting) seen in many cancer patients, boosting mitochondrial performance could alleviate debilitating symptoms and enhance their quality of life.
The widespread nature of metabolic dysfunction in aging also positions this research as particularly relevant to the global challenge of an aging population. As people age, mitochondrial decline is a pervasive issue, contributing to sarcopenia, reduced physical resilience, and increased susceptibility to chronic diseases. A therapy that could rejuvenate mitochondrial function could help maintain muscle mass and strength in older adults, promoting healthy aging and independence.
"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 Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." This broader perspective highlights the potential ripple effect of ERR activation. Enhanced mitochondrial health in muscle could reduce the metabolic burden on the cardiovascular system, potentially mitigating the progression of heart disease. In the brain, where neurons are highly energy-dependent, improved mitochondrial function could offer neuroprotective benefits, potentially impacting neurodegenerative conditions like dementia. While the study focused on muscle, the established presence of ERRs in other high-energy organs suggests that targeting them could indeed offer systemic benefits.
While specific official responses from external medical bodies or pharmaceutical companies are not detailed in the initial report, the scientific community is expected to greet these findings with considerable enthusiasm. The identification of a "druggable" target with a direct mechanism of action, particularly one linked to the master regulator PGC1α, is precisely what drug developers seek. This research provides a clear roadmap for the development of small molecule activators of ERRs, a class of compounds that are relatively straightforward to design and synthesize compared to more complex biological therapies. Experts in the field of metabolism and muscle physiology are likely to commend the Salk team for providing such a clear and compelling mechanistic understanding of ERR function, which is a crucial prerequisite for successful drug discovery.
Future Directions and Societal Impact
The Salk Institute’s latest discovery marks a pivotal moment in the quest to combat metabolic dysfunction and muscle fatigue. Understanding how estrogen-related receptors function at such a fundamental level within muscle cells creates exciting new opportunities to treat not just localized muscle issues but potentially all parts of the body affected by mitochondrial impairment.
The path forward will involve intensive research and development. Future studies will undoubtedly delve deeper into the nuanced functions and regulatory mechanisms of both the alpha- and gamma-type ERRs. Researchers will explore whether targeting ERRγ alone, or in combination with ERRα, offers distinct therapeutic advantages or tissue-specific effects. The precise molecular pathways by which ERRs interact with PGC1α and other cofactors will also be a critical area of investigation, potentially revealing additional synergistic targets.
The ultimate vision is the development of a safe and effective drug that can selectively activate ERRs, thereby enhancing mitochondrial biogenesis and function in patients who desperately need it. Such a therapeutic agent could represent a paradigm shift in how we approach a wide array of diseases, moving beyond symptomatic management to address the underlying cellular energy deficits. From improving muscle strength in patients with muscular dystrophy, to boosting endurance in individuals with chronic fatigue, to mitigating age-related decline, the potential societal impact of this research is immense. It promises not just to extend lifespan, but critically, to enhance healthspan – the period of life spent in good health and free from debilitating disease.
This groundbreaking work was supported by a robust consortium of funding bodies, 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 collaborative nature of modern scientific discovery is also underscored by the diverse team of contributing 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. Their collective expertise and dedication have paved the way for this exciting new chapter in metabolic research.
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