By Billy Candra 
The groundbreaking research, published in Proceedings of the National Academy of Sciences on May 12, 2025, spotlights a previously underappreciated family of proteins, the estrogen-related receptors (ERRs), as crucial regulators of mitochondrial health and function within muscle cells. This discovery opens a promising new avenue for therapeutic intervention in a wide range of debilitating conditions characterized by metabolic dysfunction and muscle weakness, from inherited disorders like muscular dystrophy to age-related decline and chronic diseases such as multiple sclerosis, heart disease, and dementia.
The Crucial Role of Mitochondria in Cellular Energy
At the very core of our biological existence, every cell in the human body relies on tiny, bean-shaped organelles called mitochondria. Often dubbed the "powerhouses of the cell," mitochondria are responsible for converting the food we consume into adenosine triphosphate (ATP), the primary energy currency that fuels virtually all cellular processes. This intricate process, known as cellular respiration or metabolism, is particularly vital in tissues with high energy demands, such as the brain, heart, and especially skeletal muscle, which powers all our movements, from the subtlest twitch to the most strenuous physical activity.
However, this intricate energy production system is vulnerable to dysfunction. It is estimated that approximately 1 in 5,000 individuals are born with primary mitochondrial diseases, a group of genetic disorders that severely impair mitochondrial function from birth. Beyond these inherited conditions, a vast number of people develop secondary mitochondrial dysfunction later in life. This acquired impairment is frequently associated with the natural aging process, contributing to age-related muscle weakness (sarcopenia) and fatigue. Moreover, mitochondrial dysfunction is a recognized pathological feature in a growing list of chronic diseases, including various forms of cancer, neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, cardiovascular diseases, and autoimmune conditions such as multiple sclerosis. The widespread prevalence and diverse manifestations of mitochondrial dysfunction underscore the urgent need for effective therapeutic strategies.
A Long-Standing Challenge in Treatment
Despite the significant impact of mitochondrial dysfunction on human health, effective treatments have remained elusive. Current approaches often focus on symptom management, nutritional support, or lifestyle modifications, with limited options for directly addressing the underlying cellular energy deficit. The complexity of mitochondrial biology and the multifaceted nature of the diseases it underlies have presented substantial hurdles for drug development.
This is where the recent Salk Institute findings represent a significant leap forward. The research team, led by senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, has identified estrogen-related receptors as a potent new therapeutic target capable of restoring energy supplies and combating muscle fatigue.
Ronald Evans’ Legacy: Unraveling Nuclear Hormone Receptors
Professor Ronald Evans is a titan in the field of molecular biology, renowned for his pioneering work spanning several decades. In the 1980s, his laboratory made the landmark discovery of a vast family of proteins he named "nuclear hormone receptors." These receptors are master regulators of gene expression, acting as molecular switches that, upon binding to specific hormones or other signaling molecules, attach to our DNA and control which genes are turned "on" or "off." This intricate system orchestrates a myriad of physiological processes, from metabolism and development to inflammation and reproduction. The discovery of nuclear hormone receptors revolutionized our understanding of how hormones exert their effects and paved the way for numerous drug developments targeting these pathways.
Estrogen-related receptors (ERRs) constitute a distinct branch within this extensive nuclear hormone receptor family. Though structurally similar to classic estrogen receptors, which are well-known for their roles in reproductive biology and hormone-sensitive cancers, ERRs do not bind to estrogen. For many years, their precise physiological functions remained less understood compared to their estrogen-binding counterparts. However, Evans’ lab was an early pioneer in recognizing their importance, having first discovered ERRs in 1988. From the outset, their research hinted at a critical role for ERRs in energy metabolism, a hypothesis that has now been powerfully validated.
ERRs: Indispensable Drivers of Mitochondrial Growth and Activity
The Salk team’s latest study meticulously details how ERRs play an indispensable role in regulating muscle cell metabolism, particularly under conditions of increased energy demand, such as during exercise. When muscles require more fuel to sustain activity, ERRs act as key orchestrators, initiating a process known as mitochondrial biogenesis—the cellular mechanism by which cells increase the number and enhance the energetic output of their mitochondria. This heightened mitochondrial capacity ensures a robust and sustained energy supply, crucial for muscle performance and endurance.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," explains Professor 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." This statement underscores the culmination of decades of research, highlighting the profound shift in understanding the therapeutic potential of ERRs.
The Exercise Paradox and the Search for Pharmacological Mimicry
Skeletal muscles are highly adaptive tissues. One of the most potent stimuli for enhancing muscle mitochondrial content and function is physical exercise. Regular physical activity triggers mitochondrial biogenesis, leading to increased endurance, strength, and overall metabolic health. This physiological response is precisely why exercise is universally recommended for maintaining health and preventing numerous chronic diseases.
However, the very individuals who would benefit most from enhanced mitochondrial function—those suffering from muscular dystrophy, chronic fatigue syndromes, age-related sarcopenia, or other debilitating metabolic disorders—often find sustained exercise incredibly challenging, if not impossible. Their existing muscle weakness, fatigue, and pain create a vicious cycle, preventing them from engaging in the activities that could improve their condition. This "exercise paradox" has spurred scientists to actively search for pharmacological strategies that can mimic the beneficial effects of exercise at a cellular level, without requiring physical exertion.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," says first author Weiwei Fan, a staff scientist in Evans’ 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." This foundational question guided the Salk team’s experimental design, aiming to unlock the molecular secrets behind exercise-induced metabolic adaptations.
Dissecting ERR Function: The Mouse Model Study
To definitively ascertain the role of ERRs in muscle cell metabolism, Fan and his colleagues conducted a series of meticulously designed experiments using mouse models. They genetically deleted three different forms of the estrogen-related receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of the mice. By observing the resulting effects, they could infer the unique and overlapping functions of each receptor subtype.
Their findings revealed a nuanced interplay between the ERR isoforms. The alpha receptor (ERRα) was found to be the most abundant type in muscle tissue. Interestingly, the loss of ERRα alone had only mild impacts on muscle tissue under normal, sedentary conditions. This apparent redundancy was explained by the compensatory role of the gamma receptor (ERRγ). Although ERRγ makes up only about 4% of the total estrogen-related receptors in muscle, it demonstrated a remarkable capacity to compensate for the absence of ERRα, maintaining mitochondrial function at baseline.
However, the picture changed dramatically when both ERRα and ERRγ were simultaneously deleted. This dual deletion led to severe impairments in muscle mitochondrial activity, causing significant alterations in their shape and size, and ultimately compromising overall muscle function. This finding highlighted that while ERRγ could compensate for ERRα under normal conditions, the combined absence of these key receptors exposed their critical, non-redundant roles in maintaining mitochondrial integrity.
ERRα: The Indispensable Link to Exercise-Induced Biogenesis
The researchers then turned their attention to the mystery of ERRα’s high abundance. They hypothesized that this abundance might be crucial for muscles to adapt and grow in response to exercise. To test this, the team subjected their mouse models to forced exercise on mechanical wheels. This regimen reliably triggers mitochondrial biogenesis in healthy muscles, allowing the researchers to assess whether ERRα was indeed involved in this exercise-induced adaptation.
The results were striking: losing ERRα alone completely blocked exercise-induced mitochondrial biogenesis. This pivotal finding demonstrated that while ERRγ could compensate for baseline function, ERRα was the specific and indispensable driver of the muscle’s adaptive response to physical activity, acting as the primary mediator of the beneficial metabolic effects of exercise.
The Therapeutic Advantage: Direct vs. Indirect Targets
Previous research had established that exercise-induced mitochondrial growth was largely driven by another protein known as PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α is often referred to as the "master regulator of mitochondria" throughout the body, playing a central role in energy metabolism, thermogenesis, and cellular respiration. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to DNA or genes. Instead, it functions as a coactivator, meaning it must partner with other proteins—like transcription factors—to exert its regulatory effects on gene expression. This indirect mode of action makes PGC1α a more difficult target for developing highly specific and effective therapeutic drugs.
This is where the Salk team’s new discovery offers a distinct advantage. When Evans’ lab examined muscle cells after exercise, they found a critical partnership: PGC1α was indeed collaborating with ERRα to drive mitochondrial biogenesis. Crucially, however, ERRα can bind directly to mitochondrial energetic genes and activate them. This direct interaction makes ERRα a far more appealing and tractable target for pharmacological intervention. A drug designed to specifically activate ERRα could bypass the complexities of PGC1α’s indirect mechanisms, offering a more direct and potentially more potent way to switch on the genes responsible for mitochondrial growth and activity.
Broad Implications and Future Therapeutic Horizons
The implications of these findings extend far beyond addressing simple muscle fatigue. "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," says Weiwei Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
This holistic perspective is particularly exciting given the systemic nature of metabolic dysfunction. For patients with muscular dystrophy, activating ERRα could lead to improved muscle strength and reduced degradation. For individuals experiencing age-related fatigue and sarcopenia, it could offer a path to regaining vitality and mobility. In the context of neurodegenerative diseases, where mitochondrial dysfunction is increasingly implicated in neuronal damage, enhancing energy metabolism in the brain could potentially slow disease progression or alleviate cognitive symptoms. Similarly, in heart disease, where energy demands are constant and high, boosting mitochondrial performance could improve cardiac function.
The identification of ERRα as a direct, druggable target represents a paradigm shift in the pursuit of therapies for mitochondrial disorders. The next critical steps in this research will involve the development and testing of compounds that can selectively activate ERRα. This process will require rigorous preclinical studies to ensure specificity, efficacy, and safety, followed by human clinical trials. Understanding how estrogen-related receptors function in muscle cells creates new opportunities to treat all parts of the body affected by mitochondrial dysfunction. Future research will continue to explore the intricate function and regulation of both alpha- and gamma-type receptors, which may lead to other potential therapeutic targets and refined strategies for intervention.
The collaborative nature of this groundbreaking work involved numerous dedicated researchers. Other authors who contributed to the study include 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 comprehensive research was made possible through significant financial backing from a consortium of prestigious organizations. Support was provided by 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 investment underscores the widespread recognition of the profound importance of this research in addressing a major global health challenge. The scientific community eagerly anticipates the translation of these foundational discoveries into tangible clinical benefits for patients worldwide.
