Downregulation of Ubiquitin-Dependent Proteolysis by Eicosapentaenoic Acid in Acute Starvation

Whitehouse, Alison S.; Tisdale, Michael J.

doi:10.1006/bbrc.2001.5209

Cited by 89 publications

(65 citation statements)

References 21 publications

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“…In support of this, we and others have shown that increased proteolysis in skeletal muscle during catabolic states such as fasting (54,56), tumor implantation (8,14,49,53), sepsis (25,51), diabetes (5,6,11,29,35), administration of proteolysis-inducing factor (30,31), head trauma and burn injuries (16,33), glucocorticoid administration (2), and disuse atrophy (47) is associated with two-to sevenfold increases in the gene expression of the ubiquitin-conjugating enzyme of the N-end rule, E2 14k . Others have reported about twofold increases in the gene expression of E3␣ in muscle from diabetic and septic animals (18,29,and reviewed in Ref.…”

supporting

confidence: 77%

Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Adegoke

Bédard

Roest

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Activated skeletal muscle proteolysis in catabolic states has been linked to an upregulation of the ATP-ubiquitin-dependent proteolytic system. Previous studies suggested that the N-end rule pathway is primarily responsible for the bulk of skeletal muscle proteolysis. The activity of this pathway is dependent on the 14-kDa ubiquitin-conjugating enzyme E214k (HR6B) and the ubiquitin protein ligase Ubr1. To address the requirement of E214k in muscle proteolysis, we examined muscle protein metabolism in wild-type (WT) mice and mice lacking the E214k gene (KO) in fed and fasted (48 h) states. Baseline body weight, muscle mass, and protein content were similar, and these parameters decreased similarly upon fasting in the two genotypes. There were also no effects of genotype on the rate of proteolysis in soleus muscle. The fasting-induced increase in the amount of ubiquitinated proteins was the same in WT and KO mice. The absence of any significant effect of loss of E2 14k function was not due to a compensatory induction of the closely related isoform HR6A. Total intracellular concentration of E2 14k and HR6A in the WT mice was 290 Ϯ 40 nM, but the level in the KO mice (reflecting the level of HR6A) was 110 Ϯ 9 nM. This value is about threefold the apparent Michaelis-Menten constant (K m) of E214k (ϳ40 nM) for stimulating conjugation in muscle extracts. Because the HR6A isoform has a K m of 16 nM for stimulating conjugation, the HR6A levels in the muscles of KO mice appear sufficient for supporting conjugation mediated by this pathway during fasting. ubiquitin conjugation; starvation; muscle wasting; proteasome; muscle incubation SKELETAL MUSCLE IS THE MAIN REPOSITORY of body proteins. Increased skeletal muscle protein catabolism occurs in many diseased and malnutritional states. For example, in cancer, sepsis, and diabetes, increases in muscle proteolytic rates of up to 50% are described (24,35,48,51). Because some of these conditions are also associated with suppression of muscle protein synthesis (15,43,46, and reviewed in Ref. 7), loss of muscle mass of up to 40% can occur (38, 51).The ubiquitin system is the main cytosolic proteolytic system in eukaryotes (reviewed in Refs. 12, 55). Proteins to be degraded by this pathway are first covalently conjugated through the ⑀-amino group of a lysine residue of the substrate to the carboxyl group of the terminal glycine residue of ubiquitin (reviewed in Refs. 22,36). Studies with inhibitors of distinct intracellular proteolytic pathways have shown that, in experimental tumor implantation (8, 53), starvation (59), sepsis (24, 48, 51), diabetes (11,35,38), and muscle denervation (48), increased skeletal muscle protein catabolism is attributable largely to activation of the ubiquitin-dependent proteolytic system.The conjugation of ubiquitin to proteins requires the serial actions of at least three classes of enzymes. Ubiquitin is first activated by ubiquitin-activating enzyme (E1), leading to the formation of a thiol ester bond between the carboxy-terminal glycine of ubiquiti...

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supporting

confidence: 77%

Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Adegoke

Bédard

Roest

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…The beneficial effect of EPA on skeletal muscle wasting is secondary to a decrease in muscle protein degradation by preventing the activation of the ubiquitin-proteasome pathway. This mechanism has been reported in cancer (41), hyperthermia (42), and fasting (48).…”

supporting

confidence: 61%

Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors

Castillero

Martín

López-Menduiña

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Castillero E, Martín AI, López-Menduiña M, Villanúa MA, López-Calderón A. Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors. Am J Physiol Regul Integr Comp Physiol 297: R1322-R1331, 2009. First published September 9, 2009 doi:10.1152/ajpregu.00388.2009.-Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that has anti-inflammatory and anticachectic actions. The aim of this work was to elucidate whether EPA administration is able to prevent an arthritis-induced decrease in body weight and muscle wasting in rats. Arthritis was induced by intradermal injection of Freund's adjuvant; 3 days later, nine rats received 1 g/kg EPA or coconut oil daily. All rats were killed 15 days after adjuvant injection. EPA administration decreased the external signs of arthritis and paw volume as well as liver TNF-␣ mRNA. EPA did not modify arthritis-induced decrease in food intake or body weight gain. However, EPA treatment prevented arthritis-induced increase in muscle TNF-␣ and atrogin-1, whereas it attenuated the decrease in gastrocnemius weight and the increase in MuRF1 mRNA. Arthritis not only decreased myogenic regulatory factors but also increased PCNA, MyoD, and myogenin mRNA in the gastrocnemius. Western blot analysis showed that changes in protein content followed the pattern seen with mRNA. In the control rats, EPA administration increased PCNA and MyoD mRNA and protein.In arthritic rats, EPA did not modify the stimulatory effect of arthritis on these myogenic regulatory factors. The results suggest that in experimental arthritis, in addition to its anti-inflammatory effect, EPA treatment attenuates muscle wasting by decreasing atrogin-1 and MuRF1 gene expression and increasing the transcription factors that regulate myogenesis. adjuvant-induced arthritis; ubiquitin-proteasome system; MyoD; myogenin; proliferating cell nuclear antigen CHRONIC INFLAMMATORY DISEASES such as cancer, sepsis, and rheumatoid arthritis are associated with a decrease in body weight, skeletal muscle atrophy, and cachexia. Cachexia is a complex metabolic syndrome associated with underlying

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“…Protein degradation and activation of the ubiquitin -proteasome pathway by PIF was attenuated by lactacystin, showing the specificity of the response and also by EPA, as occurs in the gastrocnemius muscle of mice bearing the cachexia-inducing MAC16 tumour (Whitehouse et al, 2001a). In contrast, the related fatty acid docosahexaenoic acid (DHA) has been shown to be ineffective in attenuating protein catabolism and increased expression of the ubiquitin -proteasome pathway (Whitehouse et al, 2001b). This shows that PIF induces proteasome expression in myotubes through an intracellular signalling cascade that is sensitive to EPA.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

2003

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Proteolysis-inducing factor (PIF), isolated from a cachexia-inducing murine tumour, has been shown to stimulate protein breakdown in C 2 C 12 myotubes. The effect was attenuated by the specific proteasome inhibitor lactacystin and there was an elevation of proteasome 'chymotrypsin-like' enzyme activity and expression of 20S proteasome a-subunits at concentrations of PIF between 2 and 16 nM. Higher concentrations of PIF had no effect. The action of PIF was attenuated by eicosapentaenoic acid (EPA) (50 mM). At a concentration of 4 nM, PIF induced a transient decrease in IkBa levels after 30 min incubation, while no effect was seen at 20 nM PIF. The level of IkBa, an NF-kB inhibitory protein, returned to normal after 60 min. Depletion of IkBa from the cytosol was not seen in myotubes pretreated with EPA, suggesting that the NF-kB/IkB complex was stabilised. At concentrations between 2 and 8 nM, PIF stimulated an increased nuclear migration of NF-kB, which was not seen in myotubes pretreated with EPA. The PIF-induced increase in chymotrypsin-like enzyme activity was also attenuated by the NF-kB inhibitor peptide SN50, suggesting that NF-kB may be involved in the PIF-induced increase in proteasome expression. The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kB accumulation in the nucleus.

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Downregulation of Ubiquitin-Dependent Proteolysis by Eicosapentaenoic Acid in Acute Starvation

Cited by 89 publications

References 21 publications

Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

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Downregulation of Ubiquitin-Dependent Proteolysis by Eicosapentaenoic Acid in Acute Starvation

Cited by 89 publications

References 21 publications

Ubiquitin-conjugating enzyme E214k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Ubiquitin-conjugating enzyme E214k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors

Increased expression of the ubiquitin – proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB

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Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice

Ubiquitin-conjugating enzyme E2_14k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice