Potential Therapeutic Role of L-Carnitine in Skeletal Muscle Oxidative Stress and Atrophy Conditions

Montesano, Angelo; Senesi, Pamela; Luzi, Livio; Benedini, Stefano; Terruzzi, Ileana

doi:10.1155/2015/646171

Cited by 37 publications

(30 citation statements)

References 49 publications

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“…In mice that are fed a high‐fructose diet which is known as an acquired model of insulin resistance, the presence of L‐carnitine reduced protein oxidation in the lens, and the decreased anti‐oxidative enzymes were recovered, thus preserving mitochondrial function 30. Moreover, the presence of L‐carnitine increases Akt phosphorylation and accelerates myotube formation in C2C12 cells31 and in the muscle of rats 32. These pleiotropic effects of L‐carnitine, including anti‐oxidative and anti‐inflammatory activities and maintaining Akt signaling, could play an important role in the protection of mitochondrial function in CKD conditions, especially in cases of higher IS accumulation, such as uremia.…”

Section: Discussionmentioning

confidence: 99%

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Enoki

Watanabe

Arake

et al. 2017

J cachexia sarcopenia muscle

131

132

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BackgroundChronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS‐targeted intervention using AST‐120, which inhibits IS accumulation, or mitochondria‐targeted intervention using L‐carnitine or teneligliptin, a dipeptidyl peptidase‐4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.MethodsThe in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6‐nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non‐treatment group and AST‐120, L‐carnitine, or teneligliptin treatment groups.ResultsIn C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC‐1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co‐incubation with an anti‐oxidant, ascorbic acid, L‐carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin‐6 and atrophy‐related factors such as myostatin and atrogin‐1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG‐1α and increased muscular autophagy, as reflected by decreased mitochondria‐rich type I fibres. An AST‐120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L‐carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.ConclusionsOur results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS‐targeted and mitochondria‐targeted interventions for treating CKD‐induced muscle atrophy and decreased exercise endurance.

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Section: Discussionmentioning

confidence: 99%

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Enoki

Watanabe

Arake

et al. 2017

J cachexia sarcopenia muscle

131

132

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“…We demonstrated that COM attachment activated Akt/GSK-3β and Snail signaling, PI3K/Akt pharmacological inhibitor could abolish these alters and inhibit dedifferentiation, indicating that Akt/GSK3β/Snail signaling plays an overarching role in COM-induced dedifferentiation. Relationships of L-carnitine and Akt/GSK3β have been reported to be contradictory in several pathogenesises [26][27][28], but whether L-carnitine is able to protect MDCK cells from COM-induced dedifferentiation through Akt/GSK3β/Snail signaling is uncertainty. In our study, L-carnitine attenuated the COM-induced activating of Akt/GSK3β/Snail signaling, considering Akt/GSK3β/Snail signaling as a contributor to the inhibitory effect of L-carnitine on cell dedifferentiation.…”

Section: Discussionmentioning

confidence: 99%

L-Carnitine Protects Renal Tubular Cells Against Calcium Oxalate Monohydrate Crystals Adhesion Through Preventing Cells From Dedifferentiation

Li¹,

Wu²,

Duan³

et al. 2016

Kidney Blood Press Res

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Background/Aims: The interactions between calcium oxalate monohydrate (COM) crystals and renal tubular epithelial cells are important for renal stone formation but still unclear. This study aimed to investigate changes of epithelial cell phenotype after COM attachment and whether L-carnitine could protect cells against subsequent COM crystals adhesion. Methods: Cultured MDCK cells were employed and E-cadherin and Vimentin were used as markers to estimate the differentiate state. AlexaFluor-488-tagged COM crystals were used in crystals adhesion experiment to distinguish from the previous COM attachment, and adhesive crystals were counted under fluorescence microscope, which were also dissolved and the calcium concentration was assessed by flame atomic absorption spectrophotometry. Results: Dedifferentiated MDCK cells induced by transforming growth factor β1 (TGF-β1) shown higher affinity to COM crystals. After exposure to COM for 48 hours, cell dedifferentiation were observed and more subsequent COM crystals could bind onto, mediated by Akt/GSK-3β/Snail signaling. L-carnitine attenuated this signaling, resulted in inhibition of cell dedifferentiation and reduction of subsequent COM crystals adhesion. Conclusions: COM attachment promotes subsequent COM crystals adhesion, by inducing cell dedifferentiation via Akt/GSK-3β/Snail signaling. L-carnitine partially abolishes cell dedifferentiation and resists COM crystals adhesion. L-carnitine, may be used as a potential therapeutic strategy against recurrence of urolithiasis.

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“…1a. These doses were chosen based on literature data [18,19]. We studied HepG2 growth capacity to evaluate the absence of cytotoxic effects.…”

Section: Cell Line Culture Conditionsmentioning

confidence: 99%

“…Our group has recently demonstrated that LC could regulate cellular anti-oxidative responses [18][19][20]26]. Since mitochondria are the primary intracellular regulator of ROS balance, LC effect on mitochondrial activity in HepG2 cells was studied.…”

Section: L-carnitine Effects On Mitochondrial Biogenesis and Anti-oximentioning

confidence: 99%

“…l-Carnitine (LC) plays a critical role in a number of intracellular and metabolic functions, such as fatty acid transport into the mitochondria, stabilization of cell membranes, and reduction of serum lipid levels [17]. Moreover, recent evidence has showed, as LC is also a potent antioxidant: in vitro studies, performing mouse myoblasts [18], rat cardiomyocytes [19] and human osteoblastic cells [20], LC supplementation decrease ROS overproduction and cellular antioxidant defense system.…”

Section: Introductionmentioning

confidence: 99%

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l-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers

Montesano

Senesi

Vacante

et al. 2019

J Endocrinol Invest

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Purpose Nonalcoholic fatty liver disease (NAFLD) is defined by excessive lipid accumulation in the liver and involves an ample spectrum of liver diseases, ranging from simple uncomplicated steatosis to cirrhosis and hepatocellular carcinoma. Accumulating evidence demonstrates that high fructose intake enhances NAFLD development and progression promoting inhibition of mitochondrial β-oxidation of long-chain fatty acids and oxidative damages. l-Carnitine (LC), involved in β-oxidation, has been used to reduce obesity caused by high-fat diet, which is beneficial to ameliorating fatty liver diseases. Moreover, in the recent years, various studies have established LC anti-oxidative proprieties. The objective of this study was to elucidate primarily the underlying anti-oxidative mechanisms of LC in an in vitro model of fructose-induced liver steatosis. Methods Human hepatoma HepG2 cells were maintained in medium supplemented with LC (5 mM LC) with or without 5 mM fructose (F) for 48 h and 72 h. In control cells, LC or F was not added to medium. Fat deposition, anti-oxidative, and mitochondrial homeostasis were investigated. Results LC supplementation decreased the intracellular lipid deposition enhancing AMPK activation. However, compound C (AMPK inhibitor-10 μM), significantly abolished LC benefits in F condition. Moreover, LC, increasing PGC1 α expression, ameliorates mitochondrial damage-F induced. Above all, LC reduced ROS production and simultaneously increased protein content of antioxidant factors, SOD2 and Nrf2. Conclusion Our data seemed to show that LC attenuate fructose-mediated lipid accumulation through AMPK activation. Moreover, LC counteracts mitochondrial damages and reactive oxygen species production restoring antioxidant cellular machine. These findings provide new insights into LC role as an AMPK activator and anti-oxidative molecule in NAFLD.

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Potential Therapeutic Role of L-Carnitine in Skeletal Muscle Oxidative Stress and Atrophy Conditions

Cited by 37 publications

References 49 publications

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

L-Carnitine Protects Renal Tubular Cells Against Calcium Oxalate Monohydrate Crystals Adhesion Through Preventing Cells From Dedifferentiation

l-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers

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