Estrogen-related receptors emerge as key to muscle energy

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Salk study finds ERRs as vital to mitochondrial regulation and potential targets for therapies addressing aging and metabolic decline.

In longevity science, one of the most pressing challenges is maintaining skeletal muscle function with age. Mitochondrial dysfunction drives sarcopenia, metabolic syndromes, and age-related fatigue. Now, researchers at the Salk Institute reveal that two nuclear receptors – estrogen-related receptors ERRα and ERRγ – play a central role in regulating mitochondrial energy production in muscle. These findings, published in PNAS, suggest that ERRs could become pivotal targets for therapies aimed at preserving muscle function and countering metabolic decline [1].

Longevity.Technology: Mitochondrial dysfunction is a core hallmark of aging, underpinning a wide array of degenerative, muscular and metabolic conditions. This new study from the Salk Institute identifies ERRα and ERRγ as master regulators of both baseline and exercise-induced mitochondrial energetics in skeletal muscle – positioning them as high-value targets for pharmacological intervention. Crucially, the findings demonstrate that activation of these estrogen-related receptors can reproduce key mitochondrial benefits typically associated with physical activity, effectively offering a molecular route to exercise mimetics. This is particularly promising for individuals who are unable to exercise due to frailty, injury or chronic disease – groups for whom muscle decline accelerates the path to dependency.

The study’s detailed dissection of ERR-mediated transcriptional control not only advances our understanding of mitochondrial biogenesis but also provides a robust framework for therapeutic development. With mitochondrial decline playing such a central role in the biology of aging, ERR agonists – several of which are already under investigation – could emerge as a foundational class of gerotherapeutics. As the longevity sector increasingly focuses on improving muscle health and energy metabolism, targeting ERRs may offer a novel and potent strategy to enhance healthspan and counteract age-associated physiological decline, and we spoke to Dr Weiwei Fan, first author and assistant professor at the Salk Institute, to find out more.

Exploring ERRs in muscle metabolism

Using muscle-specific knockout mouse models, the Salk team showed that deleting both ERRα and ERRγ caused profound mitochondrial defects – reduced DNA content, disrupted cristae, and collapsed oxidative capacity. Interestingly, even low levels of ERRγ were enough to preserve some mitochondrial function in glycolytic muscle lacking ERRα, revealing a surprising degree of energetic resilience conferred by ERRγ alone [1].

Dr Fan told Longevity.Technology: “This study helps us understand how muscles adapt to exercise and how they regulate their energy metabolism. It also shows us that ERRs are absolutely essential for this process, which makes them very attractive targets for therapies to treat metabolic disease, heart disease or muscle loss due to aging.” He believes enhancing mitochondrial energetics through ERR modulation holds real therapeutic promise: “Several ERR activators have already shown efficacy in preclinical models. Indeed, we are working with chemists and other researchers, and I believe it is only a matter of time before such compounds can be translated into therapies to help individuals with muscle disorders.”

From gene control to drug candidates

Translating these findings into therapies has proven challenging. Earlier generations of ERR agonists suffered from poor bioavailability and limited in vivo efficacy. However, new compounds developed by collaborator Dr. Thomas Burris show significantly improved pharmacological properties. “These newer compounds are particularly exciting,” said Fan, “as they overcome many of the limitations we saw with previous generations.”

A cross-section of mouse muscle tissue showing individual muscle fibers and their mitochondria (blue)

Fan and colleagues are already progressing toward translation. “One of the primary benefits of exercise in muscle is the induction of mitochondrial biogenesis and an enhancement of energetic capacity,” he told us. “Mitochondrial dysfunction is a key contributor to muscle weakness associated with aging and various diseases. Enhancing mitochondrial energetics, therefore, holds great promise for improving muscle function under these conditions.”

The team also explored how ERRα and ERRγ influence gene expression. Using CUT&TAG sequencing – a technique for mapping transcription factor binding sites – they demonstrated that ERRs bind to thousands of genomic loci, including promoter and enhancer regions of mitochondrial genes involved in respiration, the TCA cycle and fatty acid oxidation. Many of these genes are regulated by ERRα/γ heterodimers, indicating that their cooperation is not just functional, but directly genomic.

A key part of the study explored the interaction between ERRs and PGC1α, a coactivator known to stimulate mitochondrial biogenesis. The researchers found that PGC1α could not induce mitochondrial genes without ERRα, confirming a necessary partnership [1]. Although ERRγ could act independently, the presence of PGC1α amplified ERR activity. This suggests potential for combination therapies – pairing ERR agonists with AMPK activators or NAD+ boosters to enhance both the quantity and performance of mitochondria.

While ERRs are effective modulators of mitochondrial energetics in their own right, their performance may be further amplified in combination with upstream signals. “PGC1α absolutely needs ERRα to drive a robust mitochondrial biogenesis response,” Fan said. “On the flip side, ERRs on their own can still function without PGC1α, but they become even more active when PGC1α is present. That tells us there’s real potential for a synergistic effect when both are activated together.” This synergy could inform combination therapies that pair ERR agonists with AMPK activators or NAD+ precursors to enhance both mitochondrial quantity and function.

Such synergy could shape next-generation therapeutics for sarcopenia, especially when combined with upstream metabolic activators like NAD+ boosters or AMPK agonists. “It might lead to stronger, more sustained improvements in muscle function and energy metabolism,” said Fan. “That would be a big win for aging populations or anyone dealing with muscle loss related to diseases.”

Beyond muscle: potential for brain and aging pathways

Beyond muscle, ERRγ is also expressed in high-energy tissues like the brain, where mitochondrial dysfunction plays a key role in neurodegenerative diseases. However, the challenge lies in access – many synthetic compounds struggle to cross the blood–brain barrier, limiting direct ERR targeting in the brain. Still, there may be another way in. “There’s growing evidence of muscle-to-brain communication,” Fan noted, referencing myokines – muscle-derived factors that can cross into the brain and positively influence cognitive function. This opens the door to broader therapeutic potential for ERR activation, extending benefits beyond mobility and strength to brain health.

“Estrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood,” said senior author Ronald Evans, professor and March of Dimes Chair in Molecular and Developmental Biology at Salk. “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 [2].”

If mitochondria are the engines of life, then ERRs are looking increasingly like their ignition switches. By mapping and modulating these regulatory levers, researchers are moving closer to therapies that could restore strength, energy and independence – core ingredients in any blueprint for a longer, healthier life.