Abstract 12754: Dipeptidyl Peptidase-4 Inhibitor Can Ameliorate the Decreased Exercise Capacity in Heart Failure After Myocardial Infarction in Mice With the Skeletal Muscle Switch to Oxidative Fiber Type

Abstract

Background: Exercise capacity is limited in patients with heart failure (HF), which largely depends on the impaired skeletal muscle function. It has been reported that the treatment with glucagon-like peptide-1 (GLP-1), one of incretin hormon, improved exercise tolerance in HF patients. However, the effect of dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and its mechanism have not been elucidated. We thus investigated the effects of DPP-4 inhibitor, MK-0626 (sitagliptin analog), on the exercise capacity and skeletal muscle fiber type in mice model of HF after myocardial infarction (MI).

Methods: MI was created in male C57BL/6J mice, and sham operation was also performed. Each group of mice was divided into 2 groups of the treatment with or without MK-0626 (1 mg/kg/day, with normal chow); Sham (n=6), Sham+MK-0626 (n=6), MI (n=6), and MI+MK-0626 (n=6). After 4 weeks, echocardiographic and hemodynamic measurements were performed. Exercise capacity was assessed by the work (distance x body weight) and oxygen uptake (VO₂) measured during treadmill exercise. Muscle fiber type was evaluated in the limb skeletal muscle by myosin ATPase staining.

Results: Administration of MK-0626 reduced the blood glucose excursion in an oral glucose tolerance test (OGTT) and increased active GLP-1 levels. MI mice showed left ventricular (LV) dilatation and dysfunction associated with increased LV end-diastolic pressure and lung weight, which were not affected by MK-0626. Infarct size was comparable between MI and MI+MK-0626. Skeletal muscle weight did not differ between MI and Sham, and was not affected by MK-0626. However, exercise capacity was significantly reduced in MI compared to Sham (work 17±1 vs 29±1 J, p<0.05 and peak VO₂ 140±5 vs 164±3 mL/kg/min, p<0.05), and this decrease was ameliorated in MI+MK-0626 (work 22±1 J and peak VO₂ 158±3 mL/kg/min). Such effects of MK-0626 on exercise capacity were not observed in sham mice. Skeletal muscle fiber type switched from type I to IIb in MI mice by myosin-ATPase staining, and fiber type I was increased in MI+MK-0626.

Conclusions: The administration of MK-0626 into MI mice could improve exercise capacity and normalize fiber type switch, suggesting that DPP-4 inhibitor may be a novel therapeutic agent against HF.