Leucine Limitation Induces Autophagy and Activation of Lysosome-dependent Proteolysis in C2C12 Myotubes through a Mammalian Target of Rapamycin-independent Signaling Pathway

Mordier, Sylvie; Deval, Christiane; Béchet, Daniel; Tassa, Amina; Ferrara, Marc

doi:10.1074/jbc.m003633200

Cited by 188 publications

(141 citation statements)

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“…In accordance with these observations, leucine infusion decreases protein degradation in human subjects (Nair et al 1992). Moreover, in mouse C2C12 myotubes, leucine starvation accounts for 30-40 % of the maximal acceleration of protein breakdown obtained with total amino acids withdrawal (Mordier et al 2000). These authors also indicated that leucine starvation induces autophagy and as a consequence an increase in lysosomaldependent proteolysis.…”

Section: Regulation Of Muscle Protein Degradationsupporting

confidence: 71%

Leucine: a key amino acid in ageing-associated sarcopenia?

Dardevet

Rieu

Fafournoux

et al. 2003

NRR

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During ageing, a progressive loss of muscle mass has been well described in both man and rodents. This loss of proteins results from an imbalance between protein synthesis and degradation rates. Although some authors have shown a decrease of myofibrillar protein synthesis rates in human volunteers, this imbalance is not clearly apparent when basal rates of protein turnover are measured. A decrease in muscle protein synthesis stimulation was detected nevertheless in ageing rats during the postprandial period, suggesting that the 'meal signal' was altered during ageing. Many results now suggest that aged muscle is less sensitive to the stimulatory effect of amino acids at physiological concentrations but is still able to respond if the increase in aminoacidaemia is sufficiently large. Indeed amino acids play an important role in regulating muscle protein turnover both in vitro and in vivo. At the molecular level, amino acids modulate gene expression. Amino acid response elements have been characterised in the promoter of transcriptional factor CCAAT-enhancer binding protein homologous protein and asparagine synthetase genes. Among amino acids, leucine seems to play the major role in regulating the metabolic function. It inhibits proteolysis and stimulates muscle protein synthesis independently of insulin. Leucine has been shown to act as a real mediator by modulating specifically the activities of intracellular kinases linked to the translation of proteins such as phosphatidylinosinol 3Ј kinase and mammalian target of rapamycin-70 kDa ribosomal protein S6 (p70 S6K ) kinases. We recently demonstrated in vitro that protein synthesis of ageing rat muscles becomes resistant to the stimulatory effect of leucine in its physiological concentration range. However, when leucine concentration was increased greatly above its postprandial level, protein synthesis was stimulated normally. Moreover, we studied the effect of meal leucine supplementation on in vivo protein synthesis in adult and ageing rats. Leucine supplementation had no additional effect on muscle protein synthesis in adults but totally restored its stimulation in ageing rats. Whether chronic oral leucine supplementation would be beneficial for maintaining muscle protein mass in elderly men and women remains to be studied.

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Section: Regulation Of Muscle Protein Degradationsupporting

confidence: 71%

Leucine: a key amino acid in ageing-associated sarcopenia?

Dardevet

Rieu

Fafournoux

et al. 2003

NRR

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“…31 Indeed, induction of autophagy may increase the rate of protein catabolism. 60 Whether muscle wasting in septic patients is associated with elevation of autophagy requires further investigation.…”

Section: Skeletal Musclementioning

confidence: 99%

Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

126

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Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

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“…Combaret et al ( 16 ) showed that dietary leucine suppresses muscle protein degradation by inhibition of ubiquitin-proteasome dependent proteolysis in rats. Mordier et al ( 17 ) showed that leucine limitation induces formation of autophagy and activation of lysosomal-dependent proteolysis in C2C12 myotube through an mTOR-independent signaling path- way. Thus leucine administration may regulate the ubiquitin-proteasome system or autophagy-lysosome system.…”

Section: Discussionmentioning

confidence: 99%

Supplementation with Dietary Leucine to a Protein-Deficient Diet Suppresses Myofibrillar Protein Degradation in Rats

Sugawara

Ito

Nishizawa

et al. 2007

J Nutr Sci Vitaminol

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Summary Muscle mass is regulated by the synthesis and degradation of muscle protein, which in turn are affected by aging, several catabolic diseases, and malnutrition. Amino acids, particularly leucine, are known to stimulate muscle protein synthesis and suppress muscle protein degradation, although their long-term effects are unclear. The objective of our research was to elucidate whether long-term feeding of a protein-free or low-protein diet supplemented with leucine suppresses myofibrillar protein degradation. The rate of myofibrillar protein degradation was measured by the rate of release of 3-methylhistidine (MeHis) from isolated extensor digitorum longus (EDL) muscle. The weight of gastrocnemius muscle decreased in rats fed a protein-free diet for 7 d; however, a leucine-supplemented (1.5%) diet tended to suppress this decrease. The release of MeHis from EDL muscle was increased by the protein-free diet and decreased by the feeding of a diet supplemented with leucine to the level of a 20% casein diet. When rats were fed a 5% casein diet, the gastrocnemius muscle weight decreased and MeHis release from EDL muscle increased compared to those fed a 20% casein diet. However, feeding of a 5% casein diet supplemented with leucine (1.15%) reduced muscle weight loss and MeHis release. These results suggest that long-term feeding of leucine suppresses the rate of myofibrillar protein degradation and muscle weight loss in rats fed a protein-deficient diet. Key Words myofibrillar protein degradation, leucine, sarcopenia, muscle protein metabolism Many catabolic diseases and states such as burns, sepsis, and cancer induce muscle wasting due to a decreased rate of protein synthesis and an accelerated rate of protein degradation in skeletal muscle. These diseases induce progressive reduction in the muscle mass and muscle strength ( 1 , 2 ). Malnutrition also causes loss of muscle mass, which may be an important factor in the sarcopenia of aging. A protein-deficient diet reduces muscle mass ( 3 ) because dietary protein is an important factor regulating muscle protein turnover.Several studies have investigated factors regulating muscle protein turnover under catabolic conditions. Hormones such as insulin, insulin-like growth factor-1, growth hormones, and glucocorticoid are known to be factors that regulate muscle protein turnover ( 4 ). Dietary components also affect muscle protein turnover. It is well known that high-quality dietary protein maintains a higher rate of muscle growth due to higher protein synthesis than low-quality protein does ( 5 ). Essential amino acids stimulate muscle protein synthesis, whereas nonessential amino acids are ineffective ( 6 ). These increases in protein synthesis are partially explained by the effects of leucine.On the other hand, the effect of dietary protein on muscle protein degradation is not clear. We have previously shown that myofibrillar protein degradation was suppressed by refeeding of a casein diet after starvation in mice and rats, while it was not suppressed by a protein-...

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Leucine Limitation Induces Autophagy and Activation of Lysosome-dependent Proteolysis in C2C12 Myotubes through a Mammalian Target of Rapamycin-independent Signaling Pathway

Cited by 188 publications

References 45 publications

Leucine: a key amino acid in ageing-associated sarcopenia?

Leucine: a key amino acid in ageing-associated sarcopenia?

Autophagy in sepsis: Degradation into exhaustion?

Supplementation with Dietary Leucine to a Protein-Deficient Diet Suppresses Myofibrillar Protein Degradation in Rats

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