Depletion of LOXL2 improves respiratory capacity: From air-breathing fish to mammal under hypoxia

Air-breathing fish are fascinating because of their ability to survive under hypoxia for a long time by using air-breathing organs (ABOs). Fish ABOs are thought to resemble the mammal lung all along. However, the link between the two has not been studied in depth. Here, we reported a markedly improved respiratory capacity in mice under hypoxia by inhibiting lysyl oxidase-like 2 (LOXL2), inspired from the intestinal air-breathing of loach (Misgurnus anguillicaudatus). Moreover, a posterior intestine (an ABO) transcriptome analysis revealed that the deletion of Loxl2b obviously inhibited PI3K-AKT and TGF-β signaling, meanwhile, induced VEGF signaling, which could cause vasodilation and angiogenesis to improve the air-breathing ability of loach. The same phenomenon was found in LOXL2-inhibition mice under hypoxia, which significantly prolonged their living period relative to wild-type (WT) mice. In addition, compared with WT loach, Loxl2b−/− loach presented enhanced anaerobic metabolism, which could also make itself to better survive in hypoxic environment. This should be the magic of air-breathing fish! Supplied from air-breathing fish, this study provides a novel means of improving respiratory capacity in mammal under hypoxia. •Lysyl oxidase-like 2b (Loxl2b) was linked to loach intestine vascular fibrosis.•Loxl2b−/− loach showed an obviously improved intestinal air-breathing ability.•Inspiringly, we reported an improved respiratory ability in LOXL2-inhibition mice.•LOXL2 depletion inhibited PI3K-AKT/TGF-β signaling and induced VEGF signaling.