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

Nambu, Hisanori; Takada, Shingo; Fukushima, Arata; Matsumoto, Junichi; Kakutani, Naoya; Maékawa, Shohei; Shirakawa, Ryosuke; Nakano, Ikuo; Furihata, Takaaki; Katayama, Takashi; Yamanashi, Katsuma; Obata, Yuki; Saito, Akimichi; Yokota, Takashi; Kinugawa, Shintaro

doi:10.1016/j.ejphar.2019.172810

Cited by 47 publications

(39 citation statements)

References 47 publications

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“…Thus, basically, the patients who are susceptible to sarcopenia should not be prescribed SGLT2 inhibitors. On the other hand, a recent investigation demonstrated the intriguing result that Empagliflozin restored decreased exercise endurance capacity by alleviating skeletal muscle fatty acid oxidation in an animal heart failure model (82). In any case, we should carefully determine which kind of patients are optimal for the treatment with SGLT2 inhibitors.…”

Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

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Section: Future Directionsmentioning

confidence: 99%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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“…Empaglifrozin improves symptoms for diabetic sarcopenia in hyperglycemic Akita mice, though it is unclear whether there are other factors beyond the anti-diabetic effects and improving muscle mass ( Hirata et al, 2019 ). Empagliflozin also restores lowered exercise capacity in a murine heart failure model ( Nambu et al, 2020 ). The drug increases endurance capacity, but not muscle weight or muscle strength, by restoring mitochondrial fatty acid oxidation in skeletal muscle ( Nambu et al, 2020 ).…”

Section: Drugsmentioning

confidence: 99%

“…Empagliflozin also restores lowered exercise capacity in a murine heart failure model ( Nambu et al, 2020 ). The drug increases endurance capacity, but not muscle weight or muscle strength, by restoring mitochondrial fatty acid oxidation in skeletal muscle ( Nambu et al, 2020 ).…”

Section: Drugsmentioning

confidence: 99%

Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia

2020

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Recently, there has been an increased focus on the influences of mitochondrial dysfunction on various pathologies. Mitochondria are major intracellular organelles with a variety of critical roles, such as adenosine triphosphate production, metabolic modulation, generation of reactive oxygen species, maintenance of intracellular calcium homeostasis, and the regulation of apoptosis. Moreover, mitochondria are attracting attention as a therapeutic target in several diseases. Additionally, a lot of existing agents have been found to have pharmacological effects on mitochondria. This review provides an overview of the mitochondrial change in the kidney and skeletal muscle, which is often complicated with sarcopenia and chronic kidney disease (CKD). Furthermore, the pharmacological effects of therapeutics for CKD on mitochondria are explored.

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“…After the careful dissection of muscle tissue, fiber bundles were permeabilized by gentle agitation for 30 min in an ice-cold relaxing BIOPS solution (in mmol/L: CaK 2 EGTA [2.77], K 2 EGTA [7.23], Na 2 ATP [5.77], MgCl 2 ・6H 2 O [6.56], taurine [20], Na 2 phosphocreatine [15], imidazole [20], dithiothreitol [0.5], MES hydrate [50], pH 7.1) with saponin (50 μg/mL), as previously described [27,30]. After permeabilization, the fibers were rinsed twice by agitation for 10 min in an ice-cold respiration medium, MiR05 (in mmol/L: sucrose [110], K-lactobionate [60], EGTA [0.5], MgCl 2 [3], taurine [20], KH 2 PO 4 [10], 4-(2-hydroxyethyl)-piperazineethanesulfonic acid [20]), 1% BSA [pH 7.1]).…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial respiratory capacity was measured in permeabilized fibers at 37 °C with a high-resolution respirometer (Oxygraph-2k) [27,30]. The respirometer chamber was filled with 2 mL of MiR05 medium and permeabilized fibers (approximately 1.5–3.0 mg of gastrocnemius muscle) were added, followed by the substrates, ADP, and inhibitors in the following order: (1) ADP (10 mmol/L), (2) malate (2 mmol/L/step), (3) glutamate (10 mmol/L/step), (4) pyruvate (5 mmol/L/step), (5) succinate (10 mmol/L/step), (6) rotenone (0.5 μmol/L), and (7) succinate (10 mmol/L/step).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial respiration of complex II is not lower than that of complex I in mouse skeletal muscle

Maékawa

Takada

Furihata

et al. 2020

Biochemistry and Biophysics Reports

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Skeletal muscle (SKM) requires a large amount of energy, which is produced mainly by mitochondria, for their daily functioning. Of the several mitochondrial complexes, it has been reported that the dysfunction of complex II is associated with several diseases, including myopathy. However, the degree to which complex II contributes to ATP production by mitochondria remains unknown. As complex II is not included in supercomplexes, which are formed to produce ATP efficiently, we hypothesized that complex II-linked respiration was lower than that of complex I. In addition, differences in the characteristics of complex I and II activity suggest that different factors might regulate their function. The isolated mitochondria from gastrocnemius muscle was used for mitochondrial respiration measurement and immunoblotting in male C57BL/6J mice. Student paired t-tests were performed to compare means between two groups. A univariate linear regression model was used to determine the correlation between mitochondrial respiration and proteins. Contrary to our hypothesis, complex II-linked respiration was not significantly less than complex I-linked respiration in SKM mitochondria (complex I vs complex II, 3402 vs 2840 pmol/[s × mg]). Complex I-linked respiration correlated with the amount of complex I incorporated in supercomplexes (r = 0.727, p < 0.05), but not with the total amount of complex I subunits. In contrast, complex II-linked respiration correlated with the total amount of complex II (r = 0.883, p < 0.05), but not with the amount of each complex II subunit. We conclude that both complex I and II play important roles in mitochondrial respiration and that the assembly of both supercomplexes and complex II is essential for the normal functioning of complex I and II in mouse SKM mitochondria.

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

Cited by 47 publications

References 47 publications

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia

Mitochondrial respiration of complex II is not lower than that of complex I in mouse skeletal muscle

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