LA JOLLA, CA – May 12, 2025 – In a landmark discovery poised to redefine the treatment landscape for a myriad of debilitating conditions, scientists at the Salk Institute have identified a previously underestimated family of proteins, estrogen-related receptors (ERRs), as a critical key to repairing energy metabolism and combating muscle fatigue. Published today in the prestigious Proceedings of the National Academy of Sciences, the findings illuminate a promising new therapeutic pathway for individuals grappling with mitochondrial dysfunction, a pervasive cellular defect linked to aging, cancer, multiple sclerosis, heart disease, dementia, and genetic disorders like muscular dystrophy.
The study pinpoints ERRs, particularly the alpha subtype (ERRα), as indispensable drivers of mitochondrial growth and activity within muscle cells. These tiny, bean-shaped powerhouses are the cellular engines that convert food into the energy vital for life. Dysfunctional mitochondria, affecting 1 in 5,000 people from birth and countless others later in life, leave cells starved of energy, leading to a cascade of health problems ranging from profound muscle weakness to cognitive decline. The Salk team’s revelation suggests that by boosting ERR activity, scientists could develop a potent pharmacological strategy to restore energy supplies and alleviate the widespread impact of metabolic disorders.
The Pervasive Challenge of Mitochondrial Dysfunction
At the heart of every cell, mitochondria tirelessly perform the essential task of cellular respiration, turning glucose and fats into adenosine triphosphate (ATP), the body’s primary energy currency. This process is particularly critical in high-demand tissues such as muscle, brain, and heart, which require a constant and abundant supply of fuel to function optimally. When mitochondria falter, the consequences are severe and far-reaching.
Mitochondrial dysfunction manifests in a spectrum of ways. For some, it’s a congenital condition, presenting as severe developmental delays, muscle weakness, and organ failure from birth. For a much larger population, metabolic decline emerges with age, contributing to sarcopenia (age-related muscle loss), decreased cognitive function, and increased susceptibility to chronic diseases. Conditions like multiple sclerosis (MS) and cancer often involve profound metabolic reprogramming, where cells struggle to generate energy efficiently. Heart disease and dementia, too, have increasingly been linked to compromised mitochondrial health, underscoring the universal importance of these cellular powerhouses.
Despite the significant burden of mitochondrial disorders, effective treatments remain elusive. Current strategies often focus on managing symptoms or providing supportive care, rather than directly addressing the underlying cellular energy deficit. This therapeutic void has driven researchers worldwide to seek novel interventions capable of restoring mitochondrial health and function.
A Legacy of Discovery: Unearthing the Estrogen-Related Receptors
The journey to this pivotal discovery began decades ago 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 current study. In the 1980s, Dr. Evans led the landmark identification of a broad family of proteins he named "nuclear hormone receptors." These sophisticated molecular switches, activated by hormones, bind directly to our DNA, orchestrating the precise control of gene expression – turning specific genes "on" or "off" to regulate a myriad of biological processes, from development to metabolism.
Among the diverse branches of this nuclear hormone receptor family, Dr. Evans’s lab discovered the estrogen-related receptors (ERRs) in 1988. While sharing structural similarities with classic estrogen receptors, ERRs operate independently of estrogen, pursuing their own distinct regulatory roles. Their presence in metabolically active organs like the heart and brain hinted at their potential involvement in energy homeostasis. However, their precise function, especially in the context of muscle metabolism, remained largely enigmatic.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," Dr. Evans explains. "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." This deep historical context, combined with the current findings, elevates the significance of ERRs from lesser-known relatives to central players in metabolic health.
The Muscle-Mitochondria Connection: Why Exercise Matters
Skeletal muscles, the engines of our movement, are voracious consumers of energy. Their demand for ATP skyrockets during physical activity, necessitating a robust and adaptable mitochondrial infrastructure. Indeed, exercise is one of the most potent physiological stimuli for mitochondrial biogenesis – the process by which cells increase the number and efficiency of their mitochondria. This natural adaptation allows muscles to generate more fuel, enhancing endurance and strength.
However, for individuals suffering from muscular and metabolic disorders, exercise is often an insurmountable challenge. The very activity that could improve their mitochondrial health is made impossible by their underlying condition. This creates a vicious cycle of fatigue and decline, prompting scientists to search for pharmacological means to mimic the beneficial effects of exercise.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," says Dr. Weiwei Fan, a staff scientist in Dr. Evans’s 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 fundamental question laid the groundwork for the Salk team’s extensive investigation into ERRs.
Unraveling the ERR Code: Experimental Insights
To definitively determine the role of ERRs in muscle cell metabolism, Dr. Fan and his colleagues embarked on a series of meticulous experiments. The team utilized genetically modified mice, specifically deleting different forms of the estrogen-related receptors – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – within their muscle tissues. By observing the resulting cellular and physiological changes, they sought to delineate the unique contributions of each receptor subtype.
Their initial observations revealed intriguing insights into the hierarchy and redundancy of ERRs. While ERRα was the most abundant type of receptor found in muscle tissue, its isolated deletion had surprisingly mild impacts on muscle mitochondrial activity under normal, sedentary conditions. This led to a deeper investigation, which uncovered a compensatory mechanism: the ERRγ receptor, though constituting only a small fraction (around 4%) of total estrogen-related receptors, appeared capable of stepping in and largely compensating for the loss of ERRα. It was only when both ERRα and ERRγ were deleted that the researchers observed severe impairments in muscle mitochondrial activity, as well as significant alterations in their shape and size, underscoring the critical, albeit sometimes redundant, roles of these receptors.
This initial finding begged a crucial question: if ERRα is so abundant, why does its isolated loss have such mild effects? The researchers hypothesized that the true importance of ERRα might only become apparent under conditions of increased metabolic demand, such as exercise. To test this, the team put their mice on mechanical running wheels, a standard method to induce exercise-mediated mitochondrial biogenesis.
The results were striking and definitive. The mice lacking ERRα alone exhibited a complete blockade of exercise-induced mitochondrial biogenesis. Despite the physical exertion, their muscles failed to produce new mitochondria or enhance their energetic output, effectively demonstrating that ERRα is not just involved but is indispensable for the muscle’s adaptive response to exercise. This finding elegantly explained the abundance of ERRα: it acts as a primary sensor and effector for the increased energy demands of physical activity.
The Master Regulator and Its Indispensable Partner
Previous research had established PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) as a "master regulator" of mitochondria throughout the body. PGC1α is known to orchestrate mitochondrial biogenesis and function in response to various stimuli, including exercise. However, PGC1α presents a challenge for drug development: it cannot directly bind to DNA to activate genes. Instead, it relies on partnering with other proteins, like nuclear hormone receptors, to execute its regulatory functions. This indirect mode of action makes PGC1α a more complex target for therapeutic intervention.
This is where the Salk team’s findings truly shine. When Dr. Evans’s lab examined muscle cells after exercise, they discovered a critical partnership: PGC1α was actively co-activating ERRα to drive mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the ability to bind directly to mitochondrial energetic genes and switch them "on." This direct gene-binding capability positions ERRα as a far more accessible and promising target for pharmacological modulation. A drug designed to activate ERRα could, in essence, directly flip the switches that control mitochondrial performance and proliferation, bypassing the complexities of PGC1α’s indirect action.
Official Responses and Broader Implications
The implications of these findings extend far beyond individual muscle cells, offering a beacon of hope for a wide spectrum of health challenges. The ability to pharmacologically activate ERRs to enhance mitochondrial function could revolutionize how we approach diseases characterized by energy deficits.
"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," Dr. Fan emphasizes. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
For patients with muscular dystrophy, a group of genetic diseases characterized by progressive muscle weakness and degeneration, restoring mitochondrial function could significantly slow disease progression, improve muscle strength, and enhance quality of life. The research offers a potential pathway to directly address the energy crisis in their muscles, providing a novel avenue for treatment where options are currently limited.
The elderly population, frequently contending with sarcopenia and generalized fatigue due to age-related metabolic decline, could also benefit immensely. Boosting ERR activity might help maintain muscle mass and function, promoting healthy aging and independence.
In the context of cancer, where tumor cells often exhibit altered metabolism, understanding and manipulating ERRs could offer new strategies to disrupt cancer cell growth or protect healthy tissues from the metabolic stress of treatment. For multiple sclerosis and dementia, conditions affecting the brain – an organ with exceptionally high energy demands – enhancing mitochondrial function could potentially protect neurons, slow neurodegeneration, and alleviate cognitive symptoms. Similarly, heart disease, often exacerbated by impaired cardiac muscle function and energy metabolism, could see novel therapeutic approaches emerge from this research.
The Salk Institute’s discovery transforms estrogen-related receptors from scientific curiosities into potent therapeutic targets. Developing a drug that can selectively and effectively activate ERRs could represent a paradigm shift in metabolic medicine. Such a drug would not only address muscle weakness and fatigue but also potentially confer systemic benefits, revitalizing organ systems across the body.
The Road Ahead: Future Research and Collaboration
Understanding the nuanced function of estrogen-related receptors in muscle cells opens up exciting new avenues for future research. The Salk team plans to continue exploring the precise roles and regulatory mechanisms of both ERRα and ERRγ, seeking to unravel potential differences in their functions and identify additional therapeutic targets within this pathway. Further studies will also focus on developing specific ERR activators and testing their efficacy and safety in preclinical models, paving the way for eventual human clinical trials.
This groundbreaking work was the result of a collaborative effort, with other notable 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 extensive research was made possible through the generous support of numerous organizations, 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’s latest breakthrough offers a powerful new strategy in the ongoing fight against metabolic dysfunction, promising a future where millions may find renewed energy, strength, and an improved quality of life. The identification of estrogen-related receptors as direct, indispensable drivers of mitochondrial health marks a profound step forward in our understanding of cellular energy and its potential for therapeutic intervention.
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