{"id":53322,"date":"2025-05-13T07:00:37","date_gmt":"2025-05-13T14:00:37","guid":{"rendered":"https:\/\/www.salk.edu\/?post_type=disclosure&p=53322"},"modified":"2025-05-13T08:01:24","modified_gmt":"2025-05-13T15:01:24","slug":"estrogen-related-receptors-could-be-key-to-treating-metabolic-and-muscular-disorders","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/estrogen-related-receptors-could-be-key-to-treating-metabolic-and-muscular-disorders\/","title":{"rendered":"Estrogen-related receptors could be key to treating metabolic and muscular disorders"},"content":{"rendered":"

LA JOLLA\u2014A new Salk Institute study suggests estrogen-related receptors could be a key to repairing energy metabolism and muscle fatigue.<\/p>\n

Across the body, tiny bean-shaped structures called mitochondria turn the food we eat into usable energy. This cellular-level metabolism is especially important in muscle cells, which require a lot of fuel to power our movement. However, 1 in 5,000 people is born with dysfunctional mitochondria, and many others develop metabolic dysfunction later in life in association with aging or diseases like cancer, multiple sclerosis (MS), heart disease, and dementia.<\/p>\n

Mitochondrial dysfunction is difficult to treat, but recent findings from the Salk Institute show that a group of proteins called estrogen-related receptors could be a new and effective therapeutic target. The scientists discovered that estrogen-related receptors play an important role in muscle cell metabolism, especially during exercise. When our muscles need more energy, estrogen-related receptors can increase the number of mitochondria and enhance their energetic output within muscle cells.<\/p>\n

Los hallazgos, publicados en Actas de la Academia Nacional de Ciencias<\/em><\/a> on May 12, 2025, indicate that developing a drug to boost estrogen-related receptors could be a powerful way to restore energy supplies in people with metabolic disorders, such as muscular dystrophy.<\/p>\n

\"A<\/a>
A cross-section of mouse muscle tissue showing individual muscle fibers and their mitochondria (blue).
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

\u201cEstrogen-related receptors look a lot like classic estrogen receptors, but their function has been much less understood,\u201d says senior author Ronald Evans<\/a>, professor and March of Dimes Chair in Molecular and Developmental Biology at Salk. \u201cOur lab discovered estrogen-related receptors in 1988 and was one of the first to recognize their role in energy metabolism. Now we\u2019ve learned that estrogen-related receptors are indispensable<\/em> 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.\u201d<\/p>\n

In the 1980s, Evans led the landmark discovery of a family of proteins he named \u201cnuclear hormone receptors.\u201d These hormone-activated receptors attach themselves to our DNA and control which genes get turned \u201con\u201d or \u201coff.\u201d<\/p>\n

Estrogen-related receptors are one branch of this family. They are often found in parts of the body that need a lot of fuel to function, such as the heart and brain. This inspired Evans\u2019 team to explore their potential role in regulating metabolism in another high-energy organ: skeletal muscle.<\/p>\n

Muscles require a lot of energy, especially when we exercise. In fact, exercise is one of the main signals for muscle to trigger mitochondrial biogenesis, wherein a cell increases the number of its mitochondria to produce more fuel. But exercising is difficult for people with muscular and metabolic disorders, so scientists have been looking for another way to stimulate this process.<\/p>\n

\u201cMitochondria are our cells\u2019 energy factories, so the more we exercise, the more mitochondria our muscles need,\u201d says first author Weiwei Fan, a staff scientist in Evans\u2019 lab. \u201cThis got us thinking\u2014if 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.\u201d<\/p>\n

\"From<\/a>
From left: Yang Dai, Hunter Wang, Ronald Evans, and Weiwei Fan.<\/span>
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

To determine whether estrogen-related receptors played a role in muscle cell metabolism, Fan and his colleagues deleted three different forms of the receptors (alpha, beta, and gamma) in the muscle tissues of mice and examined the resulting effects.<\/p>\n

They found that while the most abundant type of receptor was the alpha receptor, loss of just this one receptor had mild impacts on muscle tissue. Additionally, the researchers found that while making up only 4% of total estrogen-related receptors, the gamma receptor was able to compensate for alpha receptor loss under normal conditions. If both alpha and gamma types were deleted, this led to serious impairments in muscle mitochondrial activity, shape, and size.<\/p>\n

So why is there such an excess of the alpha-type estrogen-related receptor (ERR\u03b1)? Hypothesizing that the answer is to help muscles adapt and grow in response to exercise, the team had its mice exercise on mechanical wheels to trigger mitochondrial biogenesis. This experiment revealed that losing ERR\u03b1 alone could entirely block exercise-induced mitochondrial biogenesis.<\/p>\n

Previous studies showed that exercise-induced mitochondrial growth was driven by another protein called PGC1\u03b1\u2014known as the master regulator of mitochondria throughout the body. The issue is, unlike nuclear hormone receptors such as ERRs, PGC1\u03b1 cannot bind to genes directly, so it relies on partner proteins to get the job done. This indirect action makes PGC1\u03b1 a more difficult target for therapeutic drug development.<\/p>\n

When Evans\u2019 lab looked at the muscle cells after exercise, they found that PGC1\u03b1 was partnering with ERR\u03b1 to drive mitochondrial biogenesis. But unlike PGC1\u03b1, ERR\u03b1 can bind directly to mitochondrial energetic genes and turn them \u201con,\u201d making it a promising target for improving muscle\u2019s mitochondrial performance.<\/p>\n

\u201cOur findings suggest that activating estrogen-related receptors could not only help fuel people\u2019s muscles, but it could also have other beneficial effects across the whole body,\u201d says Fan. \u201cImproving mitochondrial function and energy metabolism could help strengthen many different organ systems, including the brain and heart.\u201d<\/p>\n

Understanding how estrogen-related receptors function in muscle cells creates new opportunities to treat all parts of the body affected by mitochondrial dysfunction. Future research will continue to explore the function and regulation of both alpha- and gamma-type receptors, which may lead to other potential therapeutic targets.<\/p>\n

Other authors 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.<\/p>\n

The work was supported by the National Institutes of Health (P01HL147835, DK057978, DK120515, 1R21OD030076, CCSG P30CA23100, CCSG P30 CA014195, CCSG P30 CA014195, P30 AG068635), Department of the Navy (N00014-16-1-3159), Larry L. Hillblom Foundation, Inc. (2021-D-001-NET), Wu Tsai Human Performance Alliance, Henry L. Guenther Foundation, and Waitt Foundation.<\/p>","protected":false},"featured_media":53344,"template":"","faculty":[91],"disease-research":[123,176],"class_list":["post-53322","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-ronald-evans","disease-research-metabolism-and-diabetes","disease-research-mitochondrial-disease"],"acf":[],"yoast_head":"\nEstrogen-related receptors could be key to treating metabolic and muscular disorders - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/es\/news-release\/estrogen-related-receptors-could-be-key-to-treating-metabolic-and-muscular-disorders\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Estrogen-related receptors could be key to treating metabolic and muscular disorders - 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