Inotodiol from Chaga Mushroom Activated a Previously Unknown Function of the LXRβ Receptor in Muscle, Restoring Strength and Endurance in Aged Mice
Inotodiol from Chaga Mushroom Activated a Previously Unknown Function of the LXRβ Receptor in Muscle, Restoring Strength and Endurance in Aged Mice
Biologists at South Korea's Sungkyunkwan University and the biotech company AniMusCure found that inotodiol, the principal active compound in chaga, activates the LXRβ receptor in skeletal muscle. Aged mice given inotodiol showed restored mitochondrial function, reduced lipid accumulation in muscle fibers, and improved grip strength and endurance. The study was published on September 25 in Signal Transduction and Targeted Therapy, a Nature group journal.
Sarcopenia, the age-related loss of muscle mass and strength, is considered one of the leading causes of falls and loss of independence in older adults. A single dysfunction often underlies it: mitochondria, the cellular power stations that burn fat and sugar, weaken in aging muscle while fibers accumulate lipid. The proteins SIRT3 and PGC-1α maintain this system, and both decline with age.
The same laboratory showed in a related study in 2023 that extract of chaga, a bracket fungus that grows on birch trees, accelerated the recovery of damaged muscle and activated PGC-1α. In the new work, the extract was tested molecule by molecule, and inotodiol emerged as the strongest activator of the PGC-1α gene.
The molecular target of inotodiol was identified by computational prediction of protein binding: only the LXR receptor was confirmed, specifically LXRβ. In the liver the related LXRα usually predominates, whereas LXRβ is the dominant form in muscle. LXR was already known as a switch governing lipid metabolism: synthetic LXR activators had been tested against atherosclerosis but caused hepatic lipid overload and never reached the clinic. The function of LXRβ in muscle mitochondria is described for the first time in this paper.
Inotodiol causes LXRβ to bind the SIRT3 gene and recruit PPARδ, a regulator of muscular endurance; together they activate SIRT3 more strongly than either does alone, and SIRT3 in turn launches PGC-1α and mitochondrial repair. When LXRβ was knocked down in cells, inotodiol could no longer raise SIRT3 or PGC-1α, confirming the effect depends on this receptor. The synthetic LXR activator T0901317 induced lipogenic genes as effectively as inotodiol but failed to upregulate mitochondrial genes and barely recruited LXRβ to the SIRT3 gene. Although both molecules engage the same receptor, it activates different gene programs depending on which molecule drives it.
The authors state the distinction this way:
"Unlike conventional LXR agonists, inotodiol enhances mitochondrial efficiency, restores lipid balance, and reduces oxidative stress without causing adverse lipid metabolism disturbances."
In aged 20-month-old mice, several weeks of inotodiol treatment increased grip strength and running time, enlarged muscle fiber volume, reduced intramuscular lipid, and improved the neuromuscular junction. Body weight and organ weights were unchanged, while blood glucose and fatty acids decreased, indicating the effect is targeted specifically at muscle.
Two of the senior authors are founders of AniMusCure, which partially funded the study; three additional co-authors have filed a patent on inotodiol for muscle diseases. The same laboratory previously published a related study on farnesol in Science Translational Medicine, where a different compound protected aging mouse muscle through the protein Parkin. The LXRβ knockdown was performed only in cells; validation in a living mouse and in humans is the next step, according to the authors.
LXRβ joins a short list of proteins that directly govern mitochondria in aging muscle. Just days ago, the olfactory receptor OR10J5 was added to the same list: its activation also triggered assembly of new mitochondria and restored grip strength in aged mice. A mushroom brewed as tea for centuries has yielded yet another drug target for sarcopenia.