An inducible Flad1 knockout mouse model establishes its essential role in energy metabolism, muscle function and adult survival.

Abstract

The FLAD1 gene encodes the key enzyme in the biosynthesis of flavin adenine dinucleotide (FAD). As an essential cofactor of various enzymatic reactions, FAD is potentially involved in a series of crucial biological processes. Mutations in the FLAD1 gene are implicated in the pathogenesis of severe metabolic disorders, including lipid storage myopathy (LSM) and multiple acyl-CoA dehydrogenase deficiency (MADD). However, the in vivo pathophysiological consequences of systemic FLAD1 deficiency remain poorly understood. To address this, we generated a tamoxifen-inducible Flad1 knockout mouse model and characterized the phenotype of widespread FLAD1 ablation. Our results demonstrated that inducible Flad1 depletion in adult mice results in gradual lethality within approximately one month, accompanied by marked weight loss, severe spinal curvature, and muscle dysfunction. Mechanistically, Flad1 deficiency led to a significant reduction in FAD levels, resulting in decreased cellular ATP content and consequently a dysfunction of intracellular energy metabolism. Our study presents the first inducible Flad1 knockout mouse model and establishes the in vivo functional relevance of FLAD1 in maintaining metabolic homeostasis and organismal survival. Collectively, this model serves as a crucial tool not only for elucidating the molecular mechanisms underlying FLAD1 and FAD deficiency-related pathological changes, but also for evaluating potential therapeutic strategies for diseases related to FLAD1 dysfunction.