Estrogen-Related Receptors as Promising Targets for Metabolic and Muscular Disease Treatment

A recent study from the Salk Institute highlights the significant potential of estrogen-related receptors (ERRs) in addressing energy metabolism deficiencies and muscle fatigue associated with various disorders. Mitochondria, the tiny organelles responsible for producing cellular energy, are particularly critical in muscle cells, which require substantial fuel to facilitate movement. Dysfunction in mitochondria can lead to metabolic issues, which are prevalent in conditions like muscular dystrophy, cancer, multiple sclerosis, heart disease, and neurodegenerative diseases. Currently, treating mitochondrial dysfunction remains challenging, but ERRs may offer a new therapeutic pathway.

The study reveals that ERRs are key regulators of mitochondrial growth and activity in skeletal muscles, especially during physical exercise. When muscles need more energy, ERRs can boost the production of mitochondria and enhance their function within muscle cells. This discovery suggests that drugs designed to activate ERRs could help restore energy production in individuals suffering from metabolic disorders.

Senior author Ronald Evans explains that while ERRs resemble classical estrogen receptors, their functions have been less understood until now. His team traced their role back to the late 1980s when ERRs were first identified. They are highly expressed in high-energy-demand organs such as the heart, brain, and skeletal muscles, prompting researchers to investigate their influence on muscle metabolism.

In laboratory experiments, the scientists genetically modified mice to delete ERRs, focusing on three variants: alpha, beta, and gamma. Results showed that losing ERRα (alpha) significantly impaired mitochondrial function and muscle health, especially under exercise conditions. Notably, ERRγ (gamma) could compensate for ERRα deficiency under normal circumstances, but removing both resulted in severe mitochondrial and muscular impairments. Exercise induced mitochondrial biogenesis via ERRα, underscoring its central role.

Further analysis pinpointed an interaction between ERRα and PGC1α, a master regulator of mitochondrial biogenesis. Unlike PGC1α, which cannot directly bind DNA, ERRα can directly activate genes involved in mitochondrial energy production, making it an attractive target for drug development. Activating ERRs could potentially enhance mitochondrial function across various tissues, offering broad therapeutic benefits.

This research opens the door to novel treatments for muscular and metabolic disorders that involve mitochondrial dysfunction. Future efforts will focus on understanding how different ERR variants can be selectively targeted to optimize therapeutic outcomes. The findings underscore the importance of ERRs in muscle health and energy metabolism, with the potential to improve quality of life for patients with metabolic diseases.