Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure

Eur J Pharmacol. 2020 Jan 5:866:172810. doi: 10.1016/j.ejphar.2019.172810. Epub 2019 Nov 15.


Decreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle.

Keywords: Exercise intolerance; Ketone body; Mitochondria; Muscle strength; Myocardial infarction; SGLT2 inhibitor.

MeSH terms

  • 3-Hydroxybutyric Acid / blood
  • Adipose Tissue / drug effects
  • Adipose Tissue / pathology
  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Blood Glucose / metabolism
  • Disease Models, Animal
  • Fatty Acids / metabolism*
  • Glucosides / pharmacology*
  • Heart Failure / blood
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / physiopathology*
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / pathology
  • Muscle Strength / drug effects
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Oxidation-Reduction / drug effects
  • Oxidative Phosphorylation / drug effects
  • Physical Conditioning, Animal / physiology*
  • Physical Endurance / drug effects*
  • Recovery of Function / drug effects
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology


  • Benzhydryl Compounds
  • Blood Glucose
  • Fatty Acids
  • Glucosides
  • Insulin
  • Sodium-Glucose Transporter 2 Inhibitors
  • empagliflozin
  • 3-Hydroxybutyric Acid