The Activation of Glucagon-Like Peptide-1 Improves the Mitochondrial Abnormalities in Skeletal Muscle and Exercise Intolerance in Heart Failure Mice

Introduction: In patients with heart failure (HF), exercise capacity is limited due to impaired energy metabolism and mitochondrial abnormalities in the skeletal muscle. Glucagon-like peptide-1 (GLP-1), one of the incretin hormones, has been indicated to improve exercise capacity in HF patients. We investigated the effects of the treatment of a dipeptidyl peptidase (DPP)-4 inhibitor on the limited exercise capacity and mitochondrial abnormalities in the skeletal muscle in HF mice after myocardial infarction (MI). Methods and Results: C57BL/6J male mice underwent surgery to ligate the left coronary artery or sham-operation. The mice were subsequently divided at random into groups with or without the treatment providing a DPP-4 inhibitor, MK-0626 (1 mg/kg body weight/day) in the diet. Four weeks after surgery, treadmill test and echocardiography were performed in 4 groups (n=14 each). The exercise capacity was limited in the MI mice, and it was improved in the MI+MK-0626 mice without affecting the infarct size, cardiac function, and skeletal muscle weight. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, fatty acid oxidation and their quantity were reduced in the skeletal muscle of the MI mice, and these decreases were normalized in the MI+MK-0626 group, in association with the improvement of mitochondrial biogenesis via phosphorylation of AMP-activated protein kinase (AMPK)-sirtuin1 (Sirt1)-peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) signaling. Favorable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Excendin-(9-39) (150 pmol/kg body weight/min) with subcutaneous osmotic pumps in MI+MK-0626 mice. Similarly, exercise capacity and mitochondrial complex I activity were significantly improved by treatment of GLP-1 agonist, Excendin-4 (1 nmol/kg body weight/hour) with subcutaneous osmotic pumps in MI mice. Conclusions: The activation of GLP-1 receptor improves the reduced exercise capacity and mitochondrial abnormalities of skeletal muscle in HF mice after MI. The activation of GLP-1 receptor may be a novel therapeutic target against reduced exercise capacity and skeletal muscle dysfunction in HF.