LA JOLLA, CA – May 12, 2025 – In a groundbreaking discovery that promises to reshape our understanding and treatment of metabolic disorders, scientists at the Salk Institute have identified a crucial role for a group of proteins known as estrogen-related receptors (ERRs). A new study, published today in the prestigious Proceedings of the National Academy of Sciences, reveals that these receptors could be the long-sought key to repairing dysfunctional energy metabolism and alleviating debilitating muscle fatigue, offering a beacon of hope for millions worldwide grappling with conditions ranging from muscular dystrophy to the ravages of aging.
The findings illuminate a previously underappreciated mechanism by which our bodies regulate cellular energy production, particularly within the demanding environment of muscle cells. By demonstrating that ERRs are indispensable drivers of mitochondrial growth and activity, the Salk team has opened an exciting new avenue for developing therapeutics designed to restore energy supplies in individuals whose lives are hampered by metabolic deficiencies.
"Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood," explains senior author Ronald Evans, a professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk, whose lab has been at the forefront of nuclear hormone receptor research for decades. "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."
The Cellular Powerhouses: Mitochondria and Metabolism
At the very core of all life, within nearly every cell of our body, reside tiny, bean-shaped organelles called mitochondria. Often dubbed the "powerhouses of the cell," these microscopic structures are tasked with the monumental responsibility of converting the food we consume into adenosine triphosphate (ATP) – the fundamental currency of usable energy that fuels every biological process, from thought to movement. This intricate process, known as cellular respiration or metabolism, is absolutely vital for maintaining health and vitality.
The efficiency and abundance of mitochondria are particularly critical in muscle cells. Our muscles, whether performing a simple twitch or powering an intense marathon, demand an enormous and constant supply of energy. When mitochondrial function falters in these cells, the consequences can be profound, leading to severe muscle weakness, fatigue, and a cascade of other systemic issues.
A Widespread Challenge: The Burden of Mitochondrial Dysfunction
Unfortunately, mitochondrial dysfunction is a far more prevalent and insidious problem than many realize. While approximately 1 in 5,000 people are born with primary mitochondrial diseases – often severe, multi-systemic disorders resulting from genetic mutations – a much larger segment of the population develops metabolic dysfunction later in life. This acquired form is strongly associated with a spectrum of chronic, debilitating conditions and the natural process of aging itself.
Diseases such as cancer, multiple sclerosis (MS), heart disease, and neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, and various forms of dementia, all share a common thread of impaired mitochondrial function. In cancer, aberrant metabolism often fuels uncontrolled cell growth. In MS, energy deficits contribute to nerve damage and profound fatigue. Heart disease is frequently linked to compromised cardiac muscle mitochondria, impairing the heart’s pumping efficiency. And in neurodegeneration, failing brain cell mitochondria can lead to a decline in cognitive function and neuronal death. Muscular dystrophy, characterized by progressive muscle weakness and degeneration, also sees its devastating effects exacerbated by inadequate energy production within muscle tissue.
The insidious nature of mitochondrial dysfunction lies in its systemic impact. When the cellular energy supply is compromised, no organ system is truly spared. The brain, with its immense energy demands, suffers cognitive decline. The heart, working tirelessly, struggles to maintain circulation. Muscles, essential for mobility and daily tasks, become weak and easily fatigued. Despite the widespread impact and the sheer number of affected individuals, effective therapeutic strategies for mitochondrial dysfunction have remained elusive, presenting a significant unmet medical need.
Unlocking Metabolic Potential: The Role of Estrogen-Related Receptors
The Salk Institute’s latest discovery offers a glimmer of hope in this challenging landscape. The research team has pinpointed estrogen-related receptors (ERRs) as a novel and highly promising therapeutic target. These proteins, which belong to a larger family of nuclear hormone receptors, were found to play a pivotal role in regulating muscle cell metabolism, particularly under conditions of high energy demand, such as during physical activity.
The scientists observed that when muscles require more energy – a signal that typically triggers the body’s natural adaptive responses – ERRs spring into action. They effectively orchestrate an increase in both the number of mitochondria within muscle cells and enhance their overall energetic output. This dual action ensures that muscle tissue is adequately fueled, enabling it to perform optimally and recover efficiently. The findings strongly suggest that if scientists can develop drugs capable of boosting ERR activity, they could effectively restore the flagging energy supplies in people suffering from a variety of metabolic disorders, including devastating conditions like muscular dystrophy, where muscle weakness is a defining symptom.
Pioneering Insights: Ronald Evans and Nuclear Hormone Receptors
The significance of this discovery is further amplified by its historical context, rooted in decades of pioneering work by Ronald Evans and his team at the Salk Institute. Back in the 1980s, Evans led the landmark identification of an entire family of proteins he aptly named "nuclear hormone receptors." This seminal discovery revolutionized our understanding of how hormones, from steroids to thyroid hormones, exert their profound effects on the body.
Nuclear hormone receptors are a unique class of proteins that act as molecular switches. When activated by specific hormones, they bind directly to our DNA, effectively controlling which genes are turned "on" or "off." This intricate gene regulation network governs a vast array of physiological processes, including growth, development, metabolism, and reproduction.
Estrogen-related receptors (ERRs) represent a distinct branch within this extensive family. While they share structural similarities with classic estrogen receptors, their precise functions have historically been less understood. However, their pervasive presence in parts of the body characterized by exceptionally high energy demands – such as the heart, brain, and now, demonstrably, skeletal muscle – strongly hinted at a crucial metabolic role. It was this intriguing distribution that inspired Evans’ team to delve deeper into their potential as regulators of metabolism within our high-energy skeletal muscles.
The Demands of Movement: Muscle Energy and Mitochondrial Biogenesis
Skeletal muscles, the engines of our movement, are incredibly dynamic and metabolically active tissues. Their energy requirements fluctuate dramatically, from minimal demands during rest to colossal needs during strenuous exercise. To meet these varying energy budgets, muscle cells possess a remarkable adaptive capacity. One of the most critical adaptive responses is called mitochondrial biogenesis.
Mitochondrial biogenesis is the process by which a cell increases the number and/or mass of its mitochondria. When we engage in physical activity, our muscles send signals that trigger this process, effectively boosting their energy-producing capacity to cope with increased workload. This is why regular exercise leads to improved endurance and reduced fatigue – it literally builds more cellular powerhouses.
However, for individuals with muscular and metabolic disorders, engaging in the very exercise that could stimulate mitochondrial growth is often an insurmountable challenge. Their muscles are too weak, too fatigued, or too damaged to undergo the necessary exertion. This Catch-22 situation has driven scientists to relentlessly search for alternative methods – pharmacological interventions – that could bypass the need for physical exercise and directly stimulate mitochondrial biogenesis in these vulnerable patient populations.
"Mitochondria are our cells’ energy factories, so the more we exercise, the more mitochondria our muscles need," elaborates 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 fundamental question formed the core of their latest investigation.
Dissecting the Mechanism: Experimental Design and Revelatory Findings
To definitively determine whether estrogen-related receptors played a direct and significant role in muscle cell metabolism, Fan and his colleagues embarked on a meticulously designed series of experiments using mouse models. Their approach involved genetically deleting specific forms of ERRs within the muscle tissues of mice and then carefully examining the resulting physiological and cellular effects.
The Mouse Model: Unmasking ERR Function
The researchers focused on the three main forms of estrogen-related receptors: alpha (ERRα), beta (ERRβ), and gamma (ERRγ). By selectively removing these receptors, either individually or in combination, they could observe how their absence impacted mitochondrial activity, muscle function, and overall metabolic health. This precise genetic manipulation allowed the team to tease apart the specific contributions of each ERR subtype.
Alpha, Beta, Gamma: A Complex Interplay
Their initial observations revealed an intriguing hierarchy and interplay among the ERR subtypes. They found that ERRα was by far the most abundant type of receptor in muscle tissue. Surprisingly, the loss of ERRα alone had only mild impacts on muscle tissue under normal, resting conditions. This suggested a degree of redundancy or compensatory mechanisms at play.
Further investigation uncovered that ERRγ, despite making up a mere 4% of the total estrogen-related receptors, possessed a remarkable ability to compensate for the loss of ERRα under these normal conditions. This finding highlighted a sophisticated regulatory network within muscle cells, ensuring metabolic stability even when one key player is diminished.
However, the picture changed dramatically when both the alpha and gamma types of ERRs were simultaneously deleted. This dual knockout led to severe impairments in muscle mitochondrial activity, significantly altering their shape and size. The mitochondria became fewer, less functional, and structurally compromised, underscoring the critical, combined importance of ERRα and ERRγ for maintaining optimal mitochondrial health and function.
The Exercise Connection: ERRα as the Indispensable Driver
The initial finding that ERRα’s absence had only mild effects under normal conditions prompted a deeper question: why such an abundance of ERRα if its loss alone isn’t crippling? The team hypothesized that ERRα’s true significance might lie in its role in helping muscles adapt and grow in response to physiological stress, specifically exercise.
To test this hypothesis, the researchers put their ERR-deficient mice through a regimen of forced exercise on mechanical wheels. This exercise protocol was designed to rigorously trigger mitochondrial biogenesis, mimicking the natural adaptive response seen in healthy muscles. The experiment yielded a profound and conclusive result: losing ERRα alone entirely blocked exercise-induced mitochondrial biogenesis. This discovery unequivocally established ERRα as an indispensable driver of the muscle’s adaptive capacity to physical exertion, solidifying its central role in energy metabolism.
Strategic Therapeutic Targeting: ERRs vs. PGC1α
For years, another protein called PGC1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) has been recognized as the "master regulator" of mitochondria throughout the body. Previous studies had shown that exercise-induced mitochondrial growth was largely driven by PGC1α. However, PGC1α presents a significant challenge for therapeutic drug development. Unlike nuclear hormone receptors such as ERRs, PGC1α cannot bind directly to genes. Instead, it acts as a coactivator, meaning it relies on partnering with other proteins to exert its effects on gene expression. This indirect mode of action makes PGC1α a much more difficult target for developing drugs that can precisely modulate its activity.
The Salk team’s new research elegantly resolves this conundrum. When Evans’ lab meticulously examined the muscle cells after exercise, they made a critical observation: PGC1α was actively partnering with ERRα to drive mitochondrial biogenesis. This interaction is key. Critically, and unlike PGC1α, ERRα possesses the unique ability to bind directly to mitochondrial energetic genes and switch them "on." This direct binding capability makes ERRα an exceptionally promising target for pharmacological intervention. By developing drugs that specifically activate ERRα, scientists could potentially bypass the complexities of PGC1α and directly improve the mitochondrial performance and energy output of muscle cells.
Beyond Muscle: Widespread Therapeutic Potential
The implications of this breakthrough extend far beyond just muscle strength and 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 Weiwei Fan. "Improving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart."
This broader therapeutic potential is immensely significant. If ERRs can be pharmacologically targeted to enhance mitochondrial function, the ripple effects could be transformative for a wide array of diseases. Patients suffering from the cognitive decline associated with dementia could see improvements in brain energy metabolism. Individuals with heart disease might experience enhanced cardiac function. Even the pervasive fatigue experienced by patients with cancer or multiple sclerosis could be mitigated. The ability to restore cellular energy at a fundamental level holds the promise of not just treating symptoms, but addressing a core pathological mechanism underlying many chronic illnesses and the general decline associated with aging. By boosting energy production, such therapies could enhance overall quality of life, improve disease prognosis, and potentially extend healthy lifespan.
The Road Ahead: Future Research and Collaboration
Understanding precisely how estrogen-related receptors function in muscle cells creates unprecedented opportunities for developing innovative treatments that could impact virtually all parts of the body affected by mitochondrial dysfunction. The Salk team’s immediate future research will continue to delve deeper into the nuanced functions and regulatory mechanisms of both the alpha- and gamma-type receptors. This ongoing exploration may unveil additional critical pathways and lead to the identification of other potential therapeutic targets within this complex metabolic network.
This complex and impactful research was a collaborative effort, involving numerous talented scientists. Other contributing authors include Hui Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan Truitt, Ruth Yu, Annette Atkins, and Michael Downes from the Salk Institute; Tae Gyu Oh from Salk and the University of Oklahoma; and Christopher Liddle from the University of Sydney, Australia.
The work received substantial financial backing from prestigious organizations, underscoring its significance and potential. 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 robust funding highlights the broad recognition of the potential impact of this research on human health.
In conclusion, the Salk Institute’s discovery of the central role of estrogen-related receptors in regulating mitochondrial function marks a pivotal moment in metabolic medicine. By unraveling a fundamental mechanism of cellular energy control, these findings illuminate a clear path toward developing targeted therapies that could dramatically improve the lives of countless individuals suffering from metabolic disorders, muscle weakness, and the systemic effects of aging. The future of energy repair, it seems, lies within these overlooked yet powerful cellular orchestrators.
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