Recombinant human glucagon-like peptide-1 protects against chronic intermittent hypoxia by improving myocardial energy metabolism and mitochondrial biogenesis

Abstract Background and aims Obstructive sleep apnea syndrome is a chronic disease associated with intermittent hypoxia (IH) and is an important risk factor for cardiovascular disease. Glucagon-like peptide (GLP-1) is a naturally occurring incretin used as a promising therapeutic agent in the treatment of acute myocardial infarction, dilated cardiomyopathy, and advanced heart failure. However, whether GLP-1 can protect against IH-induced cardiac injury is still unclear. Accordingly, in this study, we evaluated the effects of recombinant human GLP-1 (rhGLP-1) on cardiac health in mice. Methods Mice were subjected to repetitive 5% O 2 for 30 s and 21% O 2 for 30 s, for a total of 8 h/day for 4 weeks. Subsequently, mice received subcutaneous injection of saline or rhGLP-1 (100 μg/kg, three times per day). Cardiac function, myocardial apoptosis and fibrosis, energy metabolism, and mitochondrial biogenesis were examined for evaluation of cardiac injury. Results A reduction in diastolic function (E/A ratio) in mice exposed to IH was significantly reversed by rhGLP-1. IH induced marked cardiomyocyte apoptosis and myocardial fibrosis. Additionally, IH resulted in a shift from fatty acid to glucose metabolism in the myocardium with downregulation of peroxisome proliferator-activated receptor (PPAR) α and PPARγ. Moreover, IH caused a reduction in mitochondrial DNA (mtDNA) replication and transcription, together with reduced mtDNA content and impaired mitochondrial ultrastructure. These changes were abolished by rhGLP-1 via activation of PGC-1α and Akt signaling. Conclusions rhGLP-1 protects against IH-induced cardiac injury by improving myocardial energy metabolism and enhancing the early adaptive changes of mitochondrial biogenesis.