By Billy Candra 
A groundbreaking study from the Salk Institute has illuminated a critical pathway for repairing cellular energy metabolism and combating muscle fatigue, identifying a group of proteins known as estrogen-related receptors (ERRs) as a potent new therapeutic target. Published in the prestigious Proceedings of the National Academy of Sciences on May 12, 2025, the research suggests that developing drugs to enhance ERR activity could offer a powerful strategy to restore energy supplies in individuals grappling with a spectrum of metabolic disorders and age-related decline.
The Ubiquitous Challenge of Mitochondrial Dysfunction
At the heart of every cell, 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 for virtually all cellular processes. This intricate cellular metabolism is particularly vital in muscle cells, which demand substantial fuel to facilitate movement, support physical activity, and maintain overall physiological function.
However, the efficiency of these cellular energy factories is often compromised. Mitochondrial dysfunction, a condition where mitochondria fail to produce adequate energy, is a significant and widespread health challenge. While approximately 1 in 5,000 individuals are born with genetic defects leading to dysfunctional mitochondria, a far greater number develop metabolic dysfunction later in life. This acquired impairment is frequently associated with the natural aging process, as well as a host of chronic diseases including cancer, multiple sclerosis (MS), heart disease, Alzheimer’s and other forms of dementia, and various neurodegenerative conditions. The symptoms of mitochondrial dysfunction are diverse and debilitating, ranging from profound fatigue and muscle weakness to organ system failures, significantly diminishing quality of life for millions globally.
Current therapeutic options for mitochondrial disorders are often limited, focusing primarily on symptomatic relief or supportive care rather than addressing the root cause of energy depletion. This scarcity of effective treatments underscores the urgent need for novel strategies capable of restoring mitochondrial health and function.
Salk Institute Unveils the Estrogen-Related Receptor Breakthrough
The recent findings from the Salk Institute offer a beacon of hope, pinpointing estrogen-related receptors as a promising and previously underappreciated avenue for intervention. The study meticulously demonstrates that ERRs play an indispensable role in regulating muscle cell metabolism, especially during periods of high energy demand, such as exercise. Researchers discovered that when muscles require more energy, ERRs can effectively increase both the number and energetic output of mitochondria within muscle cells, essentially boosting the cellular power supply.
"Estrogen-related receptors bear a striking resemblance to classic estrogen receptors, yet their precise function has remained much less understood until now," explains senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. Evans, a towering figure in molecular biology, has a long history with these receptors. His laboratory was responsible for the landmark discovery of ERRs in 1988, a significant follow-up to his earlier, pioneering work in the 1980s that identified and characterized the family of proteins he named "nuclear hormone receptors." These receptors are master regulators, acting as switches that bind to DNA and control which genes are turned "on" or "off" in response to hormonal signals, thereby governing a vast array of physiological processes.
Evans’ team was among the first to recognize the role of ERRs in energy metabolism. Given that ERRs are predominantly found in organs with high energy demands, such as the heart and brain, investigating their potential regulatory role in another energy-intensive organ – skeletal muscle – became a logical next step for the Salk researchers.
The Intricate Dance of ERRs and Muscle Adaptation
Skeletal muscles are voracious consumers of energy. The average adult muscle cell can contain hundreds to thousands of mitochondria, and this number can dramatically increase in response to physical training. Exercise, in fact, is one of the most potent natural signals for muscle cells to trigger mitochondrial biogenesis – the process by which cells increase their mitochondrial population to generate more fuel. However, for individuals suffering from muscular and metabolic disorders, the very act of exercising can be difficult, if not impossible, creating a cruel paradox where those most in need of mitochondrial enhancement are least able to achieve it through conventional means. This clinical dilemma has long driven scientists to search for pharmacological alternatives that could mimic the beneficial effects of exercise.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," states first author Weiwei Fan, a staff scientist in Evans’ lab. "This led us to a critical question: if we could precisely understand how exercise induces mitochondrial biogenesis, could we potentially target those same underlying mechanisms pharmacologically? The goal is to trigger this vital process in people who are too weak or ill to exercise on their own."
To unravel the role of ERRs in muscle cell metabolism, Fan and his colleagues conducted a series of elegant experiments. They selectively deleted three different forms of estrogen-related receptors—alpha (ERRα), beta (ERRβ), and gamma (ERRγ)—in the muscle tissues of mice and meticulously examined the resulting physiological effects.
Their investigations revealed nuanced insights into the functional redundancy and specialization of these receptors. While ERRα was found to be the most abundant type of receptor in muscle tissue, its isolated loss had only mild impacts under normal conditions. Interestingly, the researchers discovered that ERRγ, despite making up a mere 4% of total estrogen-related receptors, possessed a remarkable capacity to compensate for the absence of ERRα, maintaining mitochondrial function. However, the combined deletion of both ERRα and ERRγ resulted in severe impairments in muscle mitochondrial activity, significantly altering their shape and size and profoundly compromising energy production.
This observation led the team to ponder the apparent "excess" of ERRα. They hypothesized that its abundance was crucial for muscles to adapt and grow in response to the strenuous demands of exercise. To test this, they subjected their mice to exercise regimens on mechanical wheels. As expected, exercise triggered mitochondrial biogenesis in control mice. Crucially, the experiment revealed that the loss of ERRα alone was sufficient to entirely block this exercise-induced mitochondrial biogenesis. This finding unequivocally established ERRα as an indispensable driver of the muscle’s adaptive response to physical activity.
A Direct Path to Therapeutic Intervention
Previous research had implicated another protein, PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), as a "master regulator" of mitochondria throughout the body, playing a central role in exercise-induced mitochondrial growth. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes to turn them on or off; instead, it relies on partnering with other proteins to exert its effects. This indirect mode of action makes PGC1α a more complex and elusive target for small-molecule drug development, as modulating co-activator activity without unintended off-target effects is notoriously difficult.
The Salk team’s subsequent investigation into muscle cells post-exercise uncovered a critical partnership: PGC1α was indeed working in concert with ERRα to drive mitochondrial biogenesis. But what truly set ERRα apart as a therapeutic target was its ability to directly bind to the DNA sequences of mitochondrial energetic genes and activate them. This direct transcriptional control makes ERRα a far more accessible and promising target for drug development aimed at improving mitochondrial performance in muscles. A drug designed to specifically activate ERRα could, theoretically, bypass the complexities of PGC1α, offering a more precise and effective means to boost mitochondrial function.
Broader Implications and Future Horizons
The implications of these findings extend far beyond 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," notes Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart." Given that organs like the brain and heart are incredibly energy-intensive and are often impacted by mitochondrial dysfunction in diseases such as Alzheimer’s, Parkinson’s, and heart failure, the potential for systemic benefits is immense. This research opens the door to developing "exercise mimetic" drugs—compounds that could confer the metabolic benefits of physical activity without the need for strenuous exertion, a revolutionary prospect for bedridden patients, the elderly, or those with severe physical limitations.
The economic burden of metabolic diseases and age-related functional decline is staggering, running into hundreds of billions of dollars annually in healthcare costs and lost productivity. A therapeutic breakthrough that could effectively address mitochondrial dysfunction could alleviate immense suffering and significantly reduce this economic strain.
However, the path from laboratory discovery to clinical application is long and complex. Future research will need to delve deeper into the specific functions and regulatory mechanisms of both ERRα and ERRγ. Understanding the subtle differences and potential synergies between these receptor types could lead to the identification of additional therapeutic targets or strategies for selective activation, minimizing potential side effects while maximizing efficacy. Challenges in drug development will include ensuring the specificity of ERR activators, evaluating long-term safety, and conducting rigorous clinical trials to validate their effectiveness in human patients.
The 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.
This vital research received substantial support from various esteemed 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. Their foresight in funding this fundamental research has paved the way for what could become a new frontier in the treatment of widespread and debilitating conditions.
In conclusion, the Salk Institute’s discovery of estrogen-related receptors, particularly ERRα, as direct and indispensable drivers of mitochondrial biogenesis in muscle represents a profound advance in our understanding of cellular energy regulation. By offering a direct and actionable target for pharmacological intervention, this research ignites fresh optimism for developing innovative therapies to combat muscle weakness, fatigue, and the pervasive metabolic dysfunctions that challenge human health across the lifespan. The scientific community and patient advocacy groups alike will eagerly anticipate the next steps in translating this exciting laboratory breakthrough into tangible clinical benefits.
