Calcium influx drives m6A-dependent RUNX1T1 splicing to promote adipogenic commitment
Fibro-adipogenic progenitors-mediated intermuscular fat infiltration is pathognomonically tied to irreversible progression of sarcopenia. Despite elucidated Ca2+-adipogenesis crosstalk, the epigenetic Mechanisms of FAPs' metabolic reprogramming remain unclear. Here, we show that Ca2+ influx dyshomeostasis orchestrates FTO nuclear translocation via a non-canonical pathway, which directs m6A methylation-dependent alternative splicing of RUNX1T1 to downregulate the lipogenesis-suppressive RUNX1T1-L isoform. This cascade ultimately amplifies the C/EBPa-PPARy positive feedback loop. Mechanistically, Ca2+-saturation-induced CaM structural reconfiguration authorizes disassembly of the KCNQ1-CaM-FTO triplex, constituting the key molecular event governing FTO nuclear translocation. Unlike triple phenotypic rescue of RUNX1T1-L overexpression, FTO inhibition selectively restores adipogenesis while sparing stemness deficits and senescence. Building on the identified calcium-dependent mechanisms, we further uncovered a previously overlooked clinical implication: calcium channel blockers (CCBs) such as amlodipine markedly increase mesenteric fat accumulation, a latent side effect that, in severe cases, can progress to hepatic steatosis characterized by lipid vacuolization. Overall, our findings reveal a novel Ca2+ signaling-dependent epigenetic mechanism driving FAP metabolic reprogramming, while demonstrating the inherent limitations of broad-spectrum therapeutic strategies in complex pathological networks.