Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.
© 2025. The Author(s).