Vagal nerve stimulation improves mitochondrial dynamics via an M₃ receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia

Mitochondrial dynamics—fission and fusion—are associated with ischaemic heart disease ( IHD ). This study explored the protective effect of vagal nerve stimulation ( VNS ) against isoproterenol ( ISO )‐induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin‐related peptide1 (Drp1) and mitochondrial fission protein1 (Fis‐1)) and decreased the expression of fusion proteins (optic atrophy‐1 ( OPA 1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis‐1, OPA 1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore ( MPTP ) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO . Moreover, VNS activated AMP ‐activated protein kinase ( AMPK ), which was accompanied by phosphorylation of Ca 2+ /calmodulin‐dependent protein kinase kinase β (Ca MKK β) during myocardial ischaemia. Treatment with subtype‐3 of muscarinic acetylcholine receptor (M 3 R) antagonist 4‐diphenylacetoxy‐ N ‐methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M 3 R/Ca MKK β/ AMPK signalling are involved in mediating beneficial effects of VNS . This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M 3 R/Ca MKK β/ AMPK pathway, to attenuate ISO ‐induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD .