LA JOLLA, CA – May 12, 2025 – In a groundbreaking discovery that could revolutionize the treatment of metabolic disorders and age-related decline, scientists at the Salk Institute have identified a group of proteins known as estrogen-related receptors (ERRs) as crucial regulators of cellular energy production, particularly within muscle cells. This research, published today in the prestigious Proceedings of the National Academy of Sciences, suggests that targeting these receptors could be the key to repairing dysfunctional energy metabolism and alleviating the pervasive problem of muscle fatigue in millions worldwide.
The study zeroes in on the body’s fundamental energy factories: mitochondria. These microscopic, bean-shaped powerhouses convert the food we eat into adenosine triphosphate (ATP), the vital fuel that powers every cellular process, from thought to movement. Muscle cells, in particular, demand a prodigious supply of ATP to sustain even the simplest actions, let alone strenuous exercise. Yet, for a significant portion of the population, this intricate energy system falters. One in 5,000 individuals is born with congenital mitochondrial dysfunction, while countless others acquire metabolic impairments later in life, often linked to aging or debilitating diseases such as cancer, multiple sclerosis (MS), heart disease, and dementia.
"Mitochondrial dysfunction is a pervasive challenge, contributing to a wide spectrum of health issues that diminish quality of life for millions," stated Dr. Ronald Evans, senior author of the study, professor, and March of Dimes Chair in Molecular and Developmental Biology at Salk. "For decades, effective treatments have remained elusive. Our latest findings, however, present a profoundly promising new avenue: estrogen-related receptors. We’ve learned that these receptors are not merely participants but indispensable drivers of mitochondrial growth and activity in our muscles. This makes them an exceptionally compelling target to address muscle weakness and fatigue across numerous diseases involving metabolic dysfunction."
The Salk team’s research highlights how these estrogen-related receptors play a pivotal role in boosting both the quantity and energetic output of mitochondria within muscle cells, especially when energy demands surge, such as during physical activity. This revelation paves the way for the potential development of novel drugs designed to activate ERRs, thereby restoring vital energy supplies in individuals grappling with metabolic disorders like muscular dystrophy, chronic fatigue, and age-related sarcopenia.
The Silent Crisis: When Cellular Engines Fail
The human body is an exquisite symphony of cellular activity, each note powered by the ceaseless work of mitochondria. These organelles are more than just energy producers; they are central to cellular health, signaling pathways, and even programmed cell death. When mitochondria become dysfunctional, the consequences ripple throughout the entire organism, leading to a cascade of problems.
Metabolic dysfunction can manifest in myriad ways, from persistent fatigue and muscle weakness to more severe conditions like neurodegenerative diseases, cardiovascular problems, and even certain cancers. In muscle cells, compromised mitochondria mean reduced endurance, impaired recovery, and a general decline in physical capacity. For individuals with conditions like muscular dystrophy, where muscle tissue degenerates progressively, or for the elderly experiencing age-related muscle loss (sarcopenia), the inability to generate sufficient energy compounds their struggles, often rendering even simple daily tasks arduous.
Current treatment options for mitochondrial dysfunction are largely supportive, focusing on managing symptoms rather than addressing the root cause. This lack of targeted therapies underscores the urgent need for breakthroughs like the one reported by the Salk Institute. Scientists have long sought ways to bolster mitochondrial function and stimulate "mitochondrial biogenesis" – the process by which cells increase their number of mitochondria – particularly in those who are too frail or ill to engage in the physical activity that naturally triggers this vital process. The Salk study provides a compelling answer to this long-standing therapeutic challenge.
A Legacy of Discovery: Tracing the Path of Nuclear Hormone Receptors
The journey to understanding estrogen-related receptors is deeply intertwined with the pioneering work of Dr. Ronald Evans himself. In the 1980s, Evans led the landmark discovery of a vast family of proteins he aptly named "nuclear hormone receptors." These extraordinary receptors act as molecular switches, residing within the cell nucleus. When activated by specific hormones – ranging from steroids to vitamins – they bind directly to our DNA, controlling the intricate ballet of gene expression, turning genes "on" or "off" to regulate a myriad of biological processes, from development and metabolism to inflammation and reproduction. This discovery fundamentally reshaped our understanding of how hormones exert their profound effects on the body.
Estrogen-related receptors (ERRs) emerged as one intriguing branch of this expansive family. Although they bear a striking structural resemblance to classic estrogen receptors, their precise functions remained less understood for decades. Curiously, ERRs are often found in tissues with exceptionally high energy demands, such as the heart and the brain. This observation sparked a critical hypothesis within Evans’ lab: could ERRs also play a crucial, yet overlooked, role in regulating metabolism in another high-energy organ – skeletal muscle?
"Our lab first identified estrogen-related receptors back in 1988, and we were among the first to recognize their potential involvement in energy metabolism," Dr. Evans reflected. "But it has taken decades of dedicated research, building on the foundational understanding of nuclear hormone receptors, to finally pinpoint their indispensable role in muscle health. This latest research represents the culmination of a long and deliberate scientific pursuit."
The inherent challenge with many metabolic disorders and muscle-wasting diseases is that the very act of exercise, a natural stimulant for mitochondrial biogenesis, becomes difficult or even impossible for affected individuals. This presented a clear objective for the Salk researchers: to uncover the molecular mechanisms by which exercise stimulates mitochondrial growth, with the ultimate goal of mimicking these beneficial effects pharmacologically.
"Mitochondria are the true energy factories of our cells; the more we exercise, the greater the demand for more mitochondria in our muscles," explained Dr. Weiwei Fan, first author of the study and a staff scientist in Evans’ lab. "This fundamental principle led us to ask a crucial question: if we could decipher exactly how exercise induces mitochondrial biogenesis at a molecular level, could we then harness those same mechanisms to trigger this vital process in people who are too weak, too ill, or simply unable to exercise effectively?"
Unveiling the Mechanism: The Critical Role of ERRα
To systematically investigate the role of estrogen-related receptors in muscle cell metabolism, Dr. Fan and his colleagues embarked on a meticulously designed study using genetically modified mice. The team focused on the three main forms of ERRs – alpha (ERRα), beta (ERRβ), and gamma (ERRγ) – and selectively deleted them in the muscle tissues of the experimental animals. By observing the resulting physiological and cellular changes, they aimed to unravel the specific contributions of each receptor type.
Their initial observations revealed intriguing insights into the hierarchy and redundancy of these receptors. ERRα was found to be the most abundant type of estrogen-related receptor in muscle tissue. Surprisingly, however, the loss of ERRα alone had only mild impacts on muscle tissue under normal, resting conditions. The researchers discovered that ERRγ, despite making up a mere 4% of the total ERR population, possessed a remarkable capacity to compensate for the absence of ERRα, maintaining mitochondrial function at baseline levels. This compensatory mechanism suggested a complex interplay between the different ERR subtypes.
The true significance of ERRs, particularly ERRα, became strikingly clear when the researchers deleted both the alpha and gamma types simultaneously. This combined deletion led to severe and profound impairments in muscle mitochondrial activity, significantly altering their shape and size. These mice exhibited pronounced muscle weakness and fatigue, underscoring the critical, non-redundant roles that these two receptor types play in maintaining optimal muscle energy metabolism.
The Salk team then sought to understand why ERRα, despite its abundance, appeared somewhat dispensable under normal conditions, yet critical when ERRγ was also absent. They hypothesized that ERRα’s true power might be unleashed during periods of high energy demand, specifically during exercise. To test this, the mice were put through an exercise regimen on mechanical running wheels, a well-established method to induce mitochondrial biogenesis.
This experiment yielded a definitive and groundbreaking result: the loss of ERRα alone was sufficient to completely block exercise-induced mitochondrial biogenesis. In other words, without ERRα, the muscles were unable to adapt and increase their mitochondrial count in response to physical exertion, effectively crippling their capacity to generate more energy when needed most. This finding cemented ERRα’s position as an indispensable mediator of exercise-driven metabolic adaptation in muscle.
The Master Regulator and the Direct Driver: PGC1α and ERRα
Previous research had established another protein, PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body. PGC1α is known to orchestrate many aspects of mitochondrial biogenesis and function. However, PGC1α presents a significant challenge for therapeutic drug development: unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to DNA. Instead, it relies on partner proteins to attach to specific gene sequences and execute its regulatory functions. This indirect mode of action makes PGC1α a more complex and difficult target for developing drugs that can precisely modulate gene expression.
This is where the Salk team’s latest discovery truly shines. When Dr. Evans’ lab meticulously examined muscle cells after exercise, they observed a critical partnership: PGC1α was actively collaborating with ERRα to drive mitochondrial biogenesis. Crucially, unlike PGC1α, ERRα possesses the inherent ability to bind directly to the DNA sequences of mitochondrial energetic genes and switch them "on." This direct binding capability positions ERRα as an exceptionally promising and "druggable" target for improving muscle’s mitochondrial performance.
"The beauty of ERRα as a therapeutic target lies in its direct action," Dr. Fan elaborated. "We have a master regulator in PGC1α, which is like a brilliant conductor. But PGC1α needs an instrument – a direct DNA binder – to play the music of mitochondrial gene expression. ERRα is that instrument. By activating ERRα, we can directly ‘turn on’ the genes responsible for building and enhancing mitochondria, bypassing the complexities of indirect regulation."
This direct mechanism offers a clear advantage for pharmaceutical intervention. Drugs designed to activate ERRs could potentially offer a more precise and effective way to stimulate mitochondrial growth and function, effectively mimicking the beneficial effects of exercise in individuals unable to perform it. Such a pharmacological approach holds immense promise for patients suffering from a wide array of conditions marked by energy deficiency.
Broader Implications and the Future of Metabolic Health
The implications of the Salk Institute’s findings extend far beyond simply alleviating muscle fatigue. By understanding how estrogen-related receptors function in muscle cells, scientists have unlocked new opportunities to treat all parts of the body affected by mitochondrial dysfunction. Given that mitochondria are fundamental to virtually every cell, improving their function and energy metabolism through ERR activation could have profound and widespread beneficial effects.
"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 noted. "Improving mitochondrial function and energy metabolism is a foundational step that could help strengthen many different organ systems, including the brain and heart, which are also highly dependent on robust energy supplies."
For instance, conditions like Alzheimer’s disease and Parkinson’s disease, which have been increasingly linked to mitochondrial dysfunction in neuronal cells, could potentially benefit from strategies aimed at enhancing cellular energy production. Similarly, heart failure, a condition where the heart muscle struggles to pump blood efficiently, often involves impaired mitochondrial function. A therapy that boosts mitochondrial capacity could offer a novel approach to strengthening cardiac muscle.
The Salk Institute’s research marks a significant step forward in the quest for effective treatments for metabolic disorders. The identification of ERRs, particularly ERRα, as a direct and "druggable" target, opens a new frontier in drug development. Future research will undoubtedly delve deeper into the intricate functions and regulatory mechanisms of both alpha- and gamma-type receptors, potentially uncovering even more therapeutic targets within this crucial family of proteins. The hope is that these insights will lead to the development of a new generation of medicines that can restore energy, reduce fatigue, and dramatically improve the quality of life for millions suffering from a spectrum of debilitating conditions.
This monumental work was a collaborative effort, with 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 research received generous support from a consortium of distinguished institutions, 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. This collective support underscores the critical importance and broad implications of the Salk Institute’s pioneering investigations into the fundamental mechanisms of human health and disease.
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