Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies

Shingo Takada, Hisataka Sabe, Shintaro Kinugawa

Research output: Contribution to journalReview articlepeer-review

11 Citations (Scopus)


Various skeletal muscle abnormalities are known to occur in heart failure (HF) and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in patients with HF. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but this has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, that is, improve fatty acid metabolism, suppress glycolysis, and use ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, suppress anaerobic metabolism, and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.

Original languageEnglish
Pages (from-to)H117-H128
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number2
Publication statusPublished - Feb 2022

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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