Metformin Increases Mitochondrial Energy Formation in L6 Muscle Cell Cultures

Vytla, Veeravenkata S.; Ochs, Raymond S.

doi:10.1074/jbc.m113.482646

Cited by 41 publications

(29 citation statements)

References 56 publications

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“…11 In the present study, peak plasma lactate after supramaximal exercise was measured as an index of glycolysis, as suggested by Vytla and Ochs. 12 There was no significant difference in peak plasma lactate between the placebo and metformin groups (7.8 AE 2.6 vs 7.5 AE 3.0 mmol/L, respectively; P = 0.75; effect size 0.08; Fig. 4).…”

Section: Lactate Peakmentioning

confidence: 82%

Metformin improves performance in high‐intensity exercise, but not anaerobic capacity in healthy male subjects

Learsi

Bastos-Silva

Lima‐Silva

et al. 2015

Clin Exp Pharma Physio

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The aim of this study was to determine the ergogenic effects of metformin in high-intensity exercise, as well as its effects on anaerobic capacity, in healthy and physically active men. Ten subjects (mean (± standard deviation) maximal oxygen uptake (V˙O2max ) 38.6 ± 4.5 mL/kg per min) performed the following tests in a cycle ergometer: (i) an incremental test; (ii) six submaximal constant workload tests at 40%-90% (V˙O2max ); and (iii) two supramaximal tests (110% (V˙O2max ). Metformin (500 mg) or placebo was ingested 60 min before the supramaximal test. There were no significant differences between the placebo and metformin groups in terms of maximum accumulated oxygen deficit (2.8 ± 0.6 vs 3.0 ± 0.8 L, respectively; P = 0.08), lactate concentrations (7.8 ± 2.6 vs 7.5 ± 3.0 mmol/L, respectively; P = 0.75) or O2 consumed in either the last 30 s of exercise (40.4 ± 4.4 vs 39.9 ± 4.0 mL/kg per min, respectively; P = 0.35) or the first 110 s of exercise (29.0 ± 2.5 vs 29.5 ± 3.0 mL/kg per min, respectively; P = 0.42). Time to exhaustion was significantly higher after metformin than placebo ingestion (191 ± 33 vs 167 ± 32 s, respectively; P = 0.001). The fast component of V˙O2 recovery was higher in the metformin than placebo group (12.71 vs 12.18 mL/kg per min, respectively; P = 0.025). Metformin improved performance and anaerobic alactic contribution during high-intensity exercise, but had no effect on overall anaerobic capacity in healthy subjects.

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Section: Lactate Peakmentioning

confidence: 82%

Metformin improves performance in high‐intensity exercise, but not anaerobic capacity in healthy male subjects

Learsi

Bastos-Silva

Lima‐Silva

et al. 2015

Clin Exp Pharma Physio

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“…Likewise, it was shown that in permeabilized vastus lateralis muscle fibers of type 2 diabetes patients treated with metformin (2000±200 mg/day) Complex I-dependent respiratory capacity was not different compared with healthy control subjects, indicating that mitochondrial Complex I respiration is not inhibited by metformin [35]. Surprisingly, in L6 muscle cell cultures [36] and in skeletal muscle of kinase dead AMPK mice [21] metformin even increased mitochondrial energy formation. The discrepancies across the literature could be caused by differences in species, dosing regimens, muscle fiber types, and the methods used to determine the effect of metformin on the mitochondria.…”

Section: Discussionmentioning

confidence: 97%

Metformin Impairs Mitochondrial Function in Skeletal Muscle of Both Lean and Diabetic Rats in a Dose-Dependent Manner

et al. 2014

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Metformin is a widely prescribed drug for the treatment of type 2 diabetes. Previous studies have demonstrated in vitro that metformin specifically inhibits Complex I of the mitochondrial respiratory chain. This seems contraindicative since muscle mitochondrial dysfunction has been linked to the pathogenesis of type 2 diabetes. However, its significance for in vivo skeletal muscle mitochondrial function has yet to be elucidated. The aim of this study was to assess the effects of metformin on in vivo and ex vivo skeletal muscle mitochondrial function in a rat model of diabetes. Healthy (fa/+) and diabetic (fa/fa) Zucker diabetic fatty rats were treated by oral gavage with metformin dissolved in water (30, 100 or 300 mg/kg bodyweight/day) or water as a control for 2 weeks. After 2 weeks of treatment, muscle oxidative capacity was assessed in vivo using 31P magnetic resonance spectroscopy and ex vivo by measuring oxygen consumption in isolated mitochondria using high-resolution respirometry. Two weeks of treatment with metformin impaired in vivo muscle oxidative capacity in a dose-dependent manner, both in healthy and diabetic rats. Whereas a dosage of 30 mg/kg/day had no significant effect, in vivo oxidative capacity was 21% and 48% lower after metformin treatment at 100 and 300 mg/kg/day, respectively, independent of genotype. High-resolution respirometry measurements demonstrated a similar dose-dependent effect of metformin on ex vivo mitochondrial function. In conclusion, metformin compromises in vivo and ex vivo muscle oxidative capacity in Zucker diabetic fatty rats in a dose-dependent manner.

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“…We infer the latter two from the absence of a detectable effect of chronic metformin treatment on myocardial glucose uptake, lactate production, or oxygen consumption during ischaemia. Rather, the ATP-conserving effect of chronic metformin treatment may reflect enhanced mitochondrial efficiency during ischaemia (i.e., increased ATP production per mole of O 2 consumption), as observed with metformin treatment in skeletal muscle under metabolic stress [37]. Alternatively, it is possible that activation of AMPK by metformin decreased ATP utilization for anabolic processes [26].…”

Section: Discussionmentioning

confidence: 99%

Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs

Scalzo

et al. 2017

Diabetologia

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Aims Metformin is the drug most often used to treat type 2 diabetes. Evidence suggests that metformin may reduce mortality of patients with type 2 diabetes, but the mechanism of such an effect is unknown and outcomes of metformin treatment in patients without diabetes have not been determined. If metformin favorably affected mortality of patients without diabetes, it might have even broader therapeutic utility. We evaluated the effect of metformin on myocardial energetics and ischaemic ventricular fibrillation (VF) in metabolically normal pigs. Methods Domestic farm pigs were treated with metformin (30 mg/kg/day orally for 2-3 weeks, n=36) or received no treatment (n=37). Under anaesthesia, pigs underwent up to 90 min low-flow regional myocardial ischaemia followed by 45 min reperfusion. Pigs were monitored for arrhythmia, monophasic action potential morphology, hemodynamics and myocardial substrate utilization, AMPK phosphorylation, citrate synthase activity, and ATP concentration. Results Death due to VF occurred in 12% of pigs treated with metformin, compared with 50% of untreated controls (p=0.03). The anti-fibrillatory effect of metformin was associated with attenuation of action potential shortening in ischaemic myocardium (p=0.02) and of the difference in action potential duration between ischaemic and non-ischaemic regions (p<0.001) compared with untreated controls. Metformin had no effect on myocardial contractile function, oxygen consumption, or glucose or lactate utilization. However, during ischaemia metformin treatment amplified the activation of AMPK, maintained citrate synthase activity, and preserved ATP concentration in myocardium, compared with untreated controls (each p<0.05). Conclusions Chronic treatment of metabolically normal pigs with metformin at a clinically relevant dose reduces mortality from ischaemic VF. This protection is associated with preservation of myocardial energetics during ischaemia. Maintenance of myocardial ATP concentration during ischaemia likely prevents action potential shortening, heterogeneity of repolarization, and propensity for lethal arrhythmia. The findings suggest that metformin might be protective in patients without diabetes with coronary heart disease.

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Metformin Increases Mitochondrial Energy Formation in L6 Muscle Cell Cultures

Cited by 41 publications

References 56 publications

Metformin improves performance in high‐intensity exercise, but not anaerobic capacity in healthy male subjects

Metformin improves performance in high‐intensity exercise, but not anaerobic capacity in healthy male subjects

Metformin Impairs Mitochondrial Function in Skeletal Muscle of Both Lean and Diabetic Rats in a Dose-Dependent Manner

Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs

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