Abstract 13716: Dipeptidyl Peptidase-4 Inhibitor Improved Exercise Capacity in Association With Switching to Oxidative Skeletal Muscle Fiber Type in Mice With Post-infarct Heart Failure
Background: Exercise capacity is reduced in heart failure (HF) largely due to the impairment of skeletal muscle function. Glucagon-like peptide-1 (GLP-1), one of the incretin hormons, has been shown to improve exercise tolerance in HF patients. However, the effects of dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle characteristics have not been elucidated in HF.
Methods and Results: Myocardial infarction (MI) was created in male C57BL/6J mice (n=20) by ligating the left coronary artery, and sham operation was performed (n=20). They were further divided into 2 groups of the treatment with or without DPP-4 inhibitor, MK-0626 (1 mg/kg/day) for 4 weeks. MK-0626 significantly inhibited plasma DPP-4 activity by 42 % and increased plasma active GLP-1 levels by 171 %. MK-0626 did not affect infarct size from MI and MI+MK-0626 mice (53±2 vs 56±3 %, p=NS) and left ventricular function evaluated by echocardiography. In contrast, exercise capacity, measured by treadmill test with expired gas analysis, was reduced in MI mice compared to sham mice (work 17±1 vs 29±1 J, p<0.05, and peak VO2 140±5 vs 161±3 mL/kg/min, p<0.05) and was significantly ameliorated in MI+MK-0626 (work 22±1 J and peak VO2 158±3 mL/kg/min) without affecting skeletal muscle weight. A shift toward fast twitch myosin fiber type was observed in the skeletal muscle from MI mice, and this change was reversed by MK-0626, expressed as the increase in type I fiber from 14 to 24 % and the decrease in type IIb fiber from 25 to 19 %. Citrate synthase activity was significantly reduced in the skeletal muscle from MI mice by 71 % and this decrease was ameliorated in MI+MK-0626 by 175 %. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) gene expression and protein level were significantly reduced (gene expression 56 % and protein levels 64 %) in the skeletal muscle from MI mice and these changes were normalized in MI+MK-0626. These effects of MK-0626 on skeletal muscle fiber type and mitochondrial function were not observed in sham mice.
Conclusions: The administration of MK-0626 into MI mice improved exercise capacity and normalized the skeletal muscle fiber type switch. DPP-4 inhibitor may be a novel therapeutic agent against skeletal muscle dysfunction in HF.
- © 2013 by American Heart Association, Inc.