Inhibition of Kdm2a in skeletal muscle improves the metabolic capability and flexibility against the challenge of metabolic stress

The metabolic capacity and flexibility of skeletal muscle render it a critical organ in maintaining metabolic homeostasis against metabolic stress, with histone post-translational modifications playing pivotal roles in this process. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homeostasis are yet to be elucidated. Herein, we report that the mitochondria-rich slow-twitch myofibers are characterized by the significantly higher levels of H3K36me2 along with repressed Kdm2a expressions, an enzyme specifically catalyzes H3K36me2 demethylation, indicating that H3K36me2 regulates the fast-to-slow-twitch myofiber transition. Indeed, deletion or inhibition of Kdm2a promptly shifted the fuel utilization from glucose under cold challenge to lipids under obese condition by increasing the proportion of mitochondria-rich slow-twitch myofibers, which then enhanced the capability of mice against cold insult and protected the mice from high-fat-diet (HFD) induced obesity and insulin resistance. Mechanistically, Kdm2a deficiency led to a marked increase of H3K36me2 levels, which then promoted the recruitment of MRG15 to the Esrrg locus to process its pre-mRNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofibers transition. Collectively, our data support that Kdm2a could be a viable target against metabolic stress in clinical settings.