By Billy Candra 
A groundbreaking study from the Salk Institute, published in the Proceedings of the National Academy of Sciences on May 12, 2025, suggests that a class of proteins known as estrogen-related receptors (ERRs) could be a crucial therapeutic target for repairing energy metabolism and alleviating muscle fatigue. This discovery holds significant promise for the millions worldwide grappling with metabolic dysfunction, whether inherited, age-related, or secondary to debilitating diseases like cancer, multiple sclerosis (MS), heart disease, and dementia.
The Ubiquitous Role of Mitochondria in Energy Production
At the very core of cellular function, tiny, bean-shaped organelles called mitochondria serve as the body’s powerhouses, tirelessly converting the food we consume into adenosine triphosphate (ATP), the primary energy currency of cells. This intricate cellular metabolism is particularly vital in muscle cells, which demand substantial fuel to facilitate movement, support daily activities, and enable physical exertion. However, the efficiency of these cellular energy factories can falter. Approximately 1 in 5,000 individuals are born with congenital mitochondrial disorders, leading to a cascade of health issues ranging from muscle weakness to neurological impairments. Furthermore, a much larger segment of the population develops metabolic dysfunction later in life, often as an insidious consequence of aging or the progression of chronic illnesses. The global prevalence of metabolic syndrome, a cluster of conditions including high blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol levels, is estimated to affect roughly 20-25% of the adult population worldwide, underscoring the widespread challenge of metabolic health.
A Persistent Therapeutic Challenge
Despite the critical role of mitochondria, treating mitochondrial dysfunction has historically been a formidable challenge. Current therapeutic approaches are often symptomatic, addressing the manifestations of energy deficit rather than its root cause. This void in effective treatments has spurred intense research into novel pathways and molecular targets that could fundamentally restore metabolic balance. It is within this context that the Salk Institute’s latest findings emerge as a beacon of hope, identifying estrogen-related receptors as a potentially potent and previously underappreciated therapeutic avenue.
Estrogen-Related Receptors: A New Frontier in Metabolic Repair
The Salk scientists have elucidated that estrogen-related receptors play an indispensable role in regulating muscle cell metabolism, particularly during periods of increased energy demand such as exercise. Their research demonstrates that these receptors possess the remarkable capacity to increase both the number of mitochondria within muscle cells (a process known as mitochondrial biogenesis) and enhance their overall energetic output. This dual action positions ERRs as master regulators capable of boosting the cellular energy infrastructure.
"Estrogen-related receptors bear a striking resemblance to classic estrogen receptors, yet their precise function has remained significantly less understood until now," explains senior author Ronald Evans, a distinguished professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Professor Evans’s laboratory has a storied history with these receptors, having initially discovered estrogen-related receptors in 1988 and being among the first to recognize their involvement in energy metabolism. "What we’ve now conclusively learned is that estrogen-related receptors are indispensable drivers of mitochondrial growth and activity within our muscles. This revelation makes them an exceptionally promising target for developing treatments to combat muscle weakness and debilitating fatigue seen across a wide spectrum of diseases characterized by metabolic dysfunction."
A Legacy of Discovery: Nuclear Hormone Receptors
To fully appreciate the significance of this latest Salk breakthrough, it is essential to contextualize it within Professor Evans’s broader scientific legacy. In the 1980s, Evans led the pioneering discovery of a monumental family of proteins he named "nuclear hormone receptors." These extraordinary receptors act as molecular switches, responding to various hormones (such as steroid hormones, thyroid hormones, and retinoids) by binding to specific regions of our DNA. This binding event then precisely controls which genes are turned "on" or "off," thereby orchestrating a vast array of physiological processes, from development and reproduction to metabolism and immunity. This seminal work revolutionized our understanding of gene regulation and laid the foundation for numerous drug discoveries targeting these receptors, including treatments for cancer and metabolic disorders. Estrogen-related receptors represent a distinct but genetically related branch within this extensive family of nuclear hormone receptors. Their ubiquitous presence in organs with high energy demands—such as the heart, brain, and skeletal muscle—has long hinted at their metabolic significance, a hypothesis now robustly supported by the Salk team’s latest investigation.
The Energetic Demands of Muscle and the Challenge of Exercise
Skeletal muscles are metabolic titans, especially when engaged in physical activity. Exercise is, in fact, one of the most potent natural signals for muscle cells to initiate mitochondrial biogenesis, a vital adaptive process where cells increase the quantity of their mitochondria to meet heightened energy requirements. This natural mechanism allows muscles to become more efficient and resilient. However, for individuals suffering from muscular and metabolic disorders—conditions like muscular dystrophy, chronic fatigue syndrome, or the debilitating muscle wasting associated with cancer cachexia—the ability to exercise effectively, if at all, is severely compromised. This physiological barrier has prompted scientists to actively seek pharmacological alternatives that can mimic the beneficial effects of exercise by stimulating mitochondrial biogenesis.
"Mitochondria are truly our cells’ energy factories, and it stands to reason that the more we exercise, the more mitochondria our muscles need to function optimally," notes first author Weiwei Fan, a staff scientist in Evans’ laboratory. "This observation sparked our critical line of inquiry: if we could precisely understand the molecular mechanisms by which exercise induces mitochondrial biogenesis, we might then be able to pharmacologically target those very same mechanisms. Such a strategy could trigger this essential process in individuals who are simply too weak or too ill to engage in regular physical activity."
Unraveling the Role of ERR Subtypes: Alpha, Beta, and Gamma
To meticulously investigate the precise role of estrogen-related receptors in muscle cell metabolism, Fan and his research colleagues embarked on a series of rigorous experiments using genetically modified mouse models. They systematically deleted three distinct forms, or subtypes, of these receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—specifically within the muscle tissues of the mice. Subsequently, they meticulously examined the resulting physiological and cellular effects.
Their initial observations revealed that ERRα was the most abundant subtype of estrogen-related receptor present in muscle tissue. Intriguingly, the isolated loss of ERRα alone had only mild impacts on muscle tissue under normal, sedentary conditions. This suggested a degree of compensatory mechanism at play. Further investigation unveiled that the gamma receptor (ERRγ), despite constituting a mere 4% of the total estrogen-related receptors, possessed a remarkable capacity to compensate for the absence of ERRα under these baseline conditions. However, a more severe phenotype emerged when both the alpha and gamma types of estrogen-related receptors were simultaneously deleted. This dual deletion led to profound impairments in muscle mitochondrial activity, significantly altering their shape and size, and ultimately compromising the muscle’s ability to generate energy.
The Indispensable Role of ERRα in Exercise Adaptation
The apparent redundancy and compensatory mechanisms observed under normal conditions led the team to hypothesize that the significant excess of the alpha-type estrogen-related receptor (ERRα) might be specifically geared towards helping muscles adapt and grow in response to demanding physiological challenges, such as exercise. To test this hypothesis, the researchers subjected their genetically modified mice to a regimen of voluntary exercise on mechanical wheels. This exercise protocol reliably triggered mitochondrial biogenesis in control mice, providing a robust model to assess the involvement of ERRα in this crucial adaptive process. The results were unequivocal: the loss of ERRα alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This finding underscored ERRα’s critical and non-redundant role in the muscle’s adaptive response to physical exertion.
ERRα: A Direct and Promising Therapeutic Target
Previous scientific investigations had established that exercise-induced mitochondrial growth was largely orchestrated by another pivotal protein known as PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha). PGC1α is widely recognized as a "master regulator" of mitochondrial function 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 directly bind to genes. Instead, it functions as a coactivator, meaning it must rely on partner proteins to physically interact with DNA and execute its regulatory functions. This indirect mode of action makes PGC1α a considerably more complex and difficult target for the development of small-molecule drugs.
The Salk team’s subsequent analysis of muscle cells after exercise provided the missing link. They discovered that PGC1α was indeed partnering with ERRα to drive the process of mitochondrial biogenesis. Crucially, and unlike PGC1α, ERRα possesses the inherent ability to bind directly to mitochondrial energetic genes, effectively flipping the "on" switch for their expression. This direct gene-binding capability of ERRα makes it an exceptionally attractive and promising target for pharmacological interventions aimed at enhancing muscle mitochondrial performance and overall energy metabolism. The ability to directly modulate gene expression through ERRα offers a more straightforward and potentially more effective pathway for drug design.
Broader Implications and Future Horizons
The implications of these findings extend far beyond the realm of muscle fatigue. "Our findings strongly suggest that activating estrogen-related receptors could not only help fuel people’s muscles but could also elicit a cascade of other beneficial effects across the entire body," emphasizes Fan. "By improving fundamental mitochondrial function and energy metabolism, we could potentially strengthen numerous different organ systems, including vital ones like the brain and the heart, which are also highly energy-dependent." This suggests a potential systemic impact, offering hope for conditions ranging from neurodegenerative diseases to cardiovascular ailments where metabolic dysfunction plays a significant role. For instance, enhancing mitochondrial function in the brain could offer new strategies for combating cognitive decline associated with aging or diseases like Alzheimer’s, while improved cardiac mitochondrial health could bolster the heart’s resilience against various forms of heart disease.
Understanding the intricate mechanisms by which estrogen-related receptors function within muscle cells has thus unlocked a wealth of new opportunities for developing targeted treatments for all parts of the body adversely affected by mitochondrial dysfunction. The research community is particularly excited about the potential for developing "exercise mimetics"—drugs that could confer the metabolic benefits of physical activity without the need for strenuous exertion, a game-changer for bedridden patients or those with severe physical limitations. Patient advocacy groups, particularly those representing individuals with muscular dystrophy and other debilitating conditions, have expressed cautious optimism, highlighting the urgent need for novel therapies that can improve quality of life and potentially slow disease progression. A spokesperson for the Muscular Dystrophy Association, while acknowledging the early stage of the research, stated, "This work from the Salk Institute is incredibly encouraging. Any discovery that sheds new light on the fundamental mechanisms of muscle energy and offers a potential new therapeutic target is a step forward in our fight against muscular dystrophies."
Future research will undoubtedly delve deeper into the nuanced functions and precise regulatory mechanisms of both alpha- and gamma-type estrogen-related receptors. This continued exploration may well uncover additional therapeutic targets and refine our understanding of how to best leverage these powerful metabolic regulators. The journey from discovery to clinical application is often long and arduous, requiring extensive preclinical validation, safety testing, and rigorous clinical trials. However, the Salk Institute’s latest contribution marks a significant stride in our collective quest to unlock the secrets of cellular energy and translate that knowledge into tangible health benefits for humanity.
This pivotal work was made possible through the generous support of several key 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 collaborative spirit of the research was also highlighted by the diverse authorship, including Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes from Salk; Tae Gyu Oh from Salk and the University of Oklahoma; and Christopher Liddle from the University of Sydney, Australia. Their combined efforts have illuminated a new path forward in the battle against metabolic dysfunction and the pervasive issue of muscle fatigue.
