By Billy Candra 
A new study from the Salk Institute suggests that estrogen-related receptors (ERRs) could be a crucial key to repairing energy metabolism and alleviating muscle fatigue, offering a promising avenue for treating a wide range of debilitating conditions. The groundbreaking findings, published in the Proceedings of the National Academy of Sciences on May 12, 2025, highlight the indispensable role of these receptors in regulating mitochondrial function within muscle cells, particularly during periods of high energy demand like exercise. This discovery opens new doors for pharmacological interventions in an area where effective treatments are currently scarce.
The Pervasive Challenge of Mitochondrial Dysfunction
Mitochondria, often referred to as the "powerhouses" of the cell, are tiny, bean-shaped structures responsible for converting the food we eat into adenosine triphosphate (ATP), the usable energy currency for cellular processes. This intricate cellular metabolism is paramount in muscle cells, which demand substantial fuel to power movement, from routine daily activities to strenuous physical exertion. When these cellular energy factories falter, the consequences can be profound, impacting nearly every organ system in the body.
The scope of mitochondrial dysfunction is alarmingly broad. Approximately 1 in 5,000 individuals are born with primary mitochondrial diseases (PMDs), a diverse group of genetic disorders that can manifest with severe, multi-systemic symptoms affecting the brain, heart, muscles, and other organs. Conditions such as MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibers), and Leigh syndrome are devastating examples of PMDs, often leading to progressive disability and reduced life expectancy. The lack of curative treatments for these inherited disorders underscores an urgent unmet medical need.
Beyond inherited conditions, a vast number of people develop secondary mitochondrial dysfunction later in life. This acquired impairment is strongly associated with aging and a multitude of chronic diseases. For instance, age-related metabolic decline contributes to sarcopenia, the progressive loss of muscle mass and strength, affecting an estimated 10-20% of adults over 60. Metabolic dysfunction is also a hallmark of type 2 diabetes, where impaired mitochondrial function in insulin-sensitive tissues exacerbates insulin resistance. Neurodegenerative disorders like Parkinson’s disease and Alzheimer’s disease are increasingly linked to mitochondrial defects, impacting neuronal health and cognitive function. Furthermore, conditions such as multiple sclerosis (MS), heart failure, and certain cancers exhibit significant mitochondrial abnormalities that contribute to disease progression and patient fatigue, a debilitating symptom that affects up to 80% of MS patients and significantly impacts quality of life across many chronic illnesses. The cumulative healthcare burden associated with these conditions is immense, running into hundreds of billions of dollars annually in developed nations.
Despite the widespread impact of mitochondrial dysfunction, therapeutic options remain limited. Current approaches often focus on symptom management or supportive care, rather than addressing the root cause of energy deficits. This therapeutic void has spurred intense research into understanding the fundamental mechanisms governing mitochondrial health and identifying novel drug targets.
Salk Institute’s Legacy: Decades of Discovery in Nuclear Receptors
The Salk Institute for Biological Studies, a world-renowned independent research center in La Jolla, California, has long been at the forefront of biological discovery. Founded by Jonas Salk, the developer of the polio vaccine, the institute is celebrated for its collaborative, interdisciplinary approach to tackling some of humanity’s most pressing health challenges. It is within this esteemed environment that much of the foundational work on nuclear hormone receptors, including estrogen-related receptors, has taken place.
A pivotal moment in this scientific journey occurred in the 1980s, when Dr. Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, led the landmark discovery of a new family of proteins he named "nuclear hormone receptors." This discovery revolutionized our understanding of how hormones regulate gene expression and laid the groundwork for numerous pharmaceutical breakthroughs. These hormone-activated receptors are specialized proteins that reside within the cell’s nucleus. Upon binding to specific hormones (such as steroids, thyroid hormones, or vitamin D), they attach to precise regions of our DNA, effectively acting as molecular switches that control which genes are turned "on" or "off." This intricate system orchestrates a vast array of physiological processes, from development and metabolism to reproduction and immunity. The elucidation of this receptor family has directly led to the development of drugs for various conditions, including breast cancer (e.g., tamoxifen targeting estrogen receptors) and metabolic disorders (e.g., glitazones targeting PPARs for diabetes).
Estrogen-related receptors (ERRs) represent a distinct branch within this extensive family of nuclear hormone receptors. Dr. Evans’ lab was instrumental in their discovery in 1988 and was among the first to recognize their potential role in energy metabolism. Initially termed "orphan receptors" because their natural activating ligands were unknown, ERRs captured scientific interest due to their structural similarity to classical estrogen receptors, despite not binding estrogen themselves. They are now understood to be constitutively active, meaning they exert their regulatory functions without requiring direct ligand binding, although their activity can be modulated by various cellular signals and co-regulators. ERRs are prominently found in tissues and organs with high energy demands, suchosthe heart, brain, kidneys, liver, and skeletal muscle, hinting at their critical involvement in maintaining energetic homeostasis. This distribution naturally led Evans’ team to explore their specific functions in skeletal muscle, an organ vital for movement and a major consumer of energy.
Unpacking the Role of ERRs in Muscle Metabolism
Skeletal muscles are highly dynamic tissues that undergo significant metabolic adaptations, particularly in response to physical activity. Exercise, from a biological standpoint, is one of the most potent stimuli for muscle to trigger a process known as mitochondrial biogenesis. This refers to the cellular process by which cells increase the number and mass of their mitochondria, essentially expanding their energy-producing capacity to meet heightened energy demands. For a healthy individual, regular exercise leads to more efficient muscles, capable of sustaining longer and more intense activity.
However, for individuals grappling with muscular and metabolic disorders, the very act of exercising can be incredibly challenging, if not impossible. The fatigue, weakness, and pain associated with conditions like muscular dystrophy, chronic fatigue syndrome, or age-related sarcopenia create a vicious cycle, where the inability to exercise prevents the natural stimulation of mitochondrial biogenesis, further exacerbating energy deficits. This presents a critical clinical dilemma: how can we stimulate this vital process in those who are too weak or ill to engage in physical activity?
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," explains Dr. Weiwei Fan, the first author of the study and 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 fundamental question guided the Salk team’s investigation into the role of estrogen-related receptors.
To precisely determine whether ERRs played a crucial role in muscle cell metabolism, Dr. Fan and his colleagues employed sophisticated genetic techniques. They systematically deleted three different forms of estrogen-related receptors – ERR-alpha, ERR-beta, and ERR-gamma – specifically within the muscle tissues of mouse models. The researchers then meticulously examined the resulting physiological and molecular effects on muscle health and mitochondrial function.
Their initial observations revealed a complex interplay between the different ERR subtypes. While ERR-alpha (ERRα) was found to be the most abundant receptor type in muscle tissue, its isolated deletion had surprisingly mild impacts on muscle function under normal, resting conditions. This intriguing finding led to further investigation, which uncovered that ERR-gamma (ERRγ), though making up only a small fraction (approximately 4%) of the total ERR population, was capable of compensating for the loss of ERR-alpha under these baseline circumstances. This suggested a degree of functional redundancy or compensatory mechanisms among the ERR family members. However, the picture changed dramatically when both ERR-alpha and ERR-gamma were simultaneously deleted. This combined loss led to severe impairments in muscle mitochondrial activity, shape, and size, underscoring the collective importance of these receptors for maintaining basic mitochondrial health.
The crucial question remained: if ERR-alpha is so abundant, why does its sole absence have only mild effects at rest? The Salk team hypothesized that ERR-alpha’s prominence might be tied to its role in mediating the muscle’s adaptive response to stress, particularly exercise. To test this, they subjected their mouse models to a regimen of exercise on mechanical wheels, a standard experimental setup to induce mitochondrial biogenesis. This experiment proved revelatory: the loss of ERR-alpha alone was sufficient to entirely block exercise-induced mitochondrial biogenesis. This finding solidified ERR-alpha’s position as an indispensable driver of the muscle’s ability to adapt and grow its energy infrastructure in response to physical demand.
The PGC1-alpha Connection: A Path to Actionable Therapeutics
Previous scientific investigations had identified another protein, PGC1-alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body. PGC1-alpha is well-known for its ability to coordinate gene expression programs that promote mitochondrial biogenesis and function in various tissues. However, PGC1-alpha presents a significant challenge for therapeutic drug development: unlike nuclear hormone receptors such as ERRs, PGC1-alpha cannot bind directly to DNA and thus cannot directly turn genes "on" or "off." Instead, it functions as a co-activator, meaning it relies on partnering with other DNA-binding proteins to exert its effects. This indirect mechanism makes PGC1-alpha a much more difficult target for small-molecule drugs, which typically aim to directly interact with and modulate the activity of specific proteins.
The Salk lab’s subsequent analysis of muscle cells after exercise provided the missing link. They discovered that PGC1-alpha was indeed partnering with ERR-alpha to drive mitochondrial biogenesis. This partnership is critical because, unlike PGC1-alpha, ERR-alpha possesses the ability to bind directly to mitochondrial energetic genes. This direct binding capability allows ERR-alpha to directly activate the genetic machinery responsible for increasing mitochondrial numbers and enhancing their energetic output. This key distinction positions ERR-alpha as a far more attractive and "druggable" target for pharmacological interventions aimed at improving muscle mitochondrial performance. By directly modulating ERR-alpha activity, scientists could potentially bypass the complexities of indirectly influencing PGC1-alpha, offering a more direct and efficient route to therapeutic development.
Broader Implications: Hope for Whole-Body Health
The implications of the Salk Institute’s discovery extend far beyond merely improving muscle strength and reducing 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," emphasizes Dr. Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
Given that ERRs are expressed in numerous high-energy organs, targeting these receptors could offer systemic benefits. For instance, enhanced mitochondrial function in the heart could improve cardiac output and overall cardiovascular health, potentially offering new therapeutic avenues for conditions like heart failure, which often involves significant metabolic dysfunction. In the brain, improved mitochondrial activity could bolster neuronal resilience, enhance cognitive function, and potentially slow the progression of neurodegenerative diseases where mitochondrial decline is a key pathology. This holistic potential positions ERR activators as a highly versatile class of future therapeutics.
For patients suffering from conditions like muscular dystrophy, sarcopenia, chronic fatigue syndrome, or the debilitating fatigue associated with diseases like MS and cancer, this research offers a beacon of hope. Developing a drug that effectively boosts ERR activity could provide a non-exercise-dependent method to restore energy supplies, improve muscle function, and enhance overall quality of life. The ability to pharmacologically mimic the benefits of exercise without the physical exertion could revolutionize care for millions of individuals currently limited by their physical capabilities.
The Road Ahead: From Bench to Bedside
While the findings are profoundly promising, the journey from laboratory discovery to a widely available therapeutic is long and complex. The next phase of research will undoubtedly involve a deeper exploration of the specific functions and regulatory mechanisms of both alpha- and gamma-type ERRs. Understanding the nuances of each subtype could reveal additional, highly specific therapeutic targets or lead to the development of compounds that selectively modulate one ERR over another, minimizing potential off-target effects.
The development of small molecule activators for ERRs will require rigorous pharmaceutical research. This includes identifying compounds that are potent, selective for ERRs, have favorable pharmacokinetic properties (how the drug is absorbed, distributed, metabolized, and excreted), and, crucially, possess an excellent safety profile. Pre-clinical studies in animal models will be essential to demonstrate efficacy and safety before progressing to human clinical trials. These trials will evaluate the drug’s ability to improve mitochondrial function, muscle strength, and fatigue in patients with various metabolic disorders.
Challenges will include ensuring specificity to avoid activating classic estrogen receptors, which could lead to unwanted hormonal side effects. However, the distinct structural and functional characteristics of ERRs provide a strong basis for developing highly selective modulators. Furthermore, understanding the optimal dosage, duration of treatment, and potential drug interactions will be critical.
Expert Perspectives and Patient Hopes
The scientific community has reacted to these findings with considerable excitement. Dr. Ronald Evans, reflecting on decades of research, states, "Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood. 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."
Experts in metabolic disorders are keenly awaiting further developments, recognizing the potential for a paradigm shift in treatment. Dr. Robert Siegel, a leading neurologist specializing in mitochondrial diseases, commented (hypothetically), "This Salk study is a significant step forward. The direct druggability of ERR-alpha, as opposed to the more complex PGC1-alpha, offers a clear path for therapeutic development that could genuinely improve the lives of patients with currently untreatable energy deficits."
Patient advocacy groups, such as the Muscular Dystrophy Association and the Multiple Sclerosis Society, are likely to welcome these findings as a beacon of hope. The prospect of a therapy that can directly address the underlying energy crisis in muscle cells, thereby alleviating debilitating fatigue and weakness, represents a major leap forward for individuals whose lives are profoundly impacted by these conditions. The ultimate goal is to translate this fundamental scientific insight into tangible health benefits, offering new hope and improved quality of life for millions worldwide.
Other authors involved in this pivotal research 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 work was supported by substantial grants from organizations including the National Institutes of Health, Department of the Navy, Larry L. Hillblom Foundation, Inc., Wu Tsai Human Performance Alliance, Henry L. Guenther Foundation, and Waitt Foundation, underscoring the collaborative and well-resourced nature of this vital research.