Loss of SREBF1 disrupts lipid signaling and causes slow muscle fiber degeneration.

SREBF1, encoding the lipogenic transcription factor SREBP1, has been linked to lean mass by human genomics. We used a CRISPR-Cas9 srebf1 zebrafish knockout combined with LC-MS/MS lipidomics, RNA-seq, Lugol-enhanced micro-CT imaging, and functional assays. Srebp1 loss disrupted slow-fiber organization, increased locomotion in larvae, and reduced muscle mass in adults. This knockout muscle showed altered fatty acid composition, reduced arachidonoylethanolamide (AEA), elevated palmitoylethanolamide (PEA), broad remodeling of polyunsaturated fatty (PUFA) acid-derived mediators, and differential expression of cardiolipin-pathway genes. Integrated transcriptomic-lipidomic analysis revealed srebf1-centered connections to myogenic regulators and calcium and lipid signaling, paralleling selective atrophy and loss of slow oxidative fibers under overfeeding and aging. Our data supports a model in which Srebp1 functions as a fiber-type-specific survival checkpoint that maintains lipid compositional and cardiolipin homeostasis, and whose disruption reprograms lipid mediators to drive slow-to-fast fiber switching and slow-fiber degeneration relevant to sarcopenia and sarcopenic obesity.