Contribution of the ubiquitin-proteasome pathway to overall muscle proteolysis in hypercatabolic patients

Biolo, Gianni; Bosutti, Alessandra; Iscra, F.; Toigo, G.; Gullo, Antonino; Guarnieri, Gianfranco

doi:10.1053/meta.2000.6236

Cited by 39 publications

(21 citation statements)

References 7 publications

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“…This pathway is responsible for the majority of proteolysis in skeletal muscle (41) and has been implicated in muscle wasting in several disease states (29,35). Increased expression of genes for various components of this pathway has been observed in several muscle-wasting conditions (6,23,49) and has been shown to correlate with muscle protein breakdown (6). No differences in the expression of ubiquitin, E2 14k , C2 subunit, or E3 ligases were found between HS and LS rats in this study.…”

Section: Discussionsupporting

confidence: 40%

Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis

Persinger

Janssen–Heininger²,

Wing³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis. Am J Physiol Endocrinol Metab 284: E1001-E1008, 2003. First published February 11, 2003 10.1152/ajpendo.00517.2002.-Heart failure is often characterized by skeletal muscle atrophy. The mechanisms underlying muscle wasting, however, are not fully understood. We studied 30 Dahl salt-sensitive rats (10 male, 20 female) fed either a high-salt (HS; n ϭ 15) or a low-salt (LS; n ϭ 15) diet. This strain develops cardiac hypertrophy and failure when fed a HS diet. LS controls were matched to HS rats for gender and duration of diet. Body mass, food intake, and muscle mass and composition were measured. Skeletal muscle protein synthesis was measured by isotope dilution. An additional group of 27 rats (HS, n ϭ 16; LS; n ϭ 11) were assessed for expression of genes regulating protein breakdown and apoptosis. Gastrocnemius and plantaris muscles weighed less (16 and 22%, respectively) in HS than in LS rats (P Ͻ 0.01). No differences in soleus or tibialis anterior weights were found. Differences in muscle mass were abolished after data were expressed relative to body size, because HS rats tended (P ϭ 0.094) to weigh less. Lower body mass in HS rats was related to a 16% reduction (P Ͻ 0.01) in food intake. No differences in muscle protein or DNA content, the protein-to-DNA ratio, or muscle protein synthesis were found. Finally, no differences in skeletal muscle gene expression were found to suggest increased protein breakdown or apoptosis in HS rats. Our results suggest that muscle wasting in this model of heart failure is not associated with alterations in skeletal muscle metabolism. Instead, muscle atrophy was related to reduced body weight secondary to decreased food intake. These findings argue against the notion that heart failure is characterized by a skeletal muscle myopathy that predisposes to atrophy. atrophy; isotope; ubiquitin proteasome pathway; cytokine IN BOTH HUMAN AND ANIMAL MODELS, heart failure is frequently characterized by skeletal muscle atrophy (14,22,33,40,43). Loss of skeletal muscle contributes to exercise intolerance (20, 43), a cardinal symptom of heart failure, and increases morbidity (1, 39) and mortality (5). Knowledge of the mechanisms underlying muscle atrophy in heart failure, however, is limited.A number of hypotheses have been put forth to explain muscle atrophy in heart failure (4, 37, 45). Each of the mechanisms forwarded in these hypotheses must ultimately affect the regulation of skeletal muscle protein or cell mass. Muscle atrophy can occur during net negative protein balance, in which protein breakdown exceeds synthesis, during net negative muscle cell balance, in which the loss of muscle cells exceeds replacement, or during a combination of these two events. Studies in both humans and animal models suggest that heart failure is associated with alterations in the regulation of skeletal muscle protein synthesis (40), protein breakdown (36), and apoptosis (47) that may predispose to s...

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Section: Discussionsupporting

confidence: 40%

Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis

Persinger

Janssen–Heininger²,

Wing³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…In patients with early lung cancer, however no increase in mRNAs for components of the ubiquitin-proteasome pathway were found in muscle, even in depleted patients, but mRNAs for a lysosomal protease, cathepsin B were increased [47]. In trauma patients a correlation was found between ubiquitin mRNA levels and proteolysis rates in leg muscle [48], and increased levels of transcripts for ubiquitin-proteasome pathway components, calcium-dependent and lysosomal proteases have been demonstrated in head trauma patients with negative nitrogen balance and raised whole-body proteolysis rates [49]. Cachectic acquired immunodeficiency syndrome (AIDS) patients were found to have raised ubiquitin and proteasome subunit mRNAs in muscle [50], and correcting acidosis in subjects with renal failure led to improved nutritional status and lowered muscle ubiquitin mRNA levels [51].…”

Section: The Pathways Of Protein Synthesis and Proteolysis In Musclementioning

confidence: 89%

Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease

Jagoe¹,

Engelen²

2003

European Respiratory Journal

104

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Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease. R.T. Jagoe, M.P.K.J. Engelen. #ERS Journals Ltd 2003. ABSTRACT: Loss of skeletal muscle mass is now recognised as an important feature of chronic obstructive pulmonary disease (COPD) which contributes to symptoms and influences prognosis. The changes in skeletal muscle remain poorly understood, largely because only a few studies have been performed to define the adaptations in whole body and muscle protein metabolism in COPD.The first sections of this review summarise background information about skeletal muscle wasting in COPD, and focuses on the studies concerned with amino acid profiles and protein synthesis and degradation rates. To aid interpretation some discussion of the techniques commonly used is included.A variety of different catabolic factors may determine whether chronic obstructive pulmonary disease patients become cachectic. The precise role for each one of these factors as well as the intracellular pathways activated in muscle as a result of chronic obstructive pulmonary disease are unknown and remain to be defined. Details of the actions of a range of different catabolic factors and potential mechanisms will be discussed. A significant proportion of patients with chronic obstructive pulmonary disease (COPD) develop peripheral skeletal muscle wasting and weakness [1,2]. Loss of skeletal muscle mass is reflected by the reduction in fat-free mass (FFM) observed in y20-40% of patients with COPD [3,4], and this has a number of consequences: 1) many studies have now shown that lower FFM is associated with reduced exercise tolerance [3,[5][6][7]. 2) Because muscle power is directly proportional to cross-sectional area, loss of muscle mass is also associated with reduced peripheral muscle strength in COPD [5,8,9]. 3) Many patients with COPD suffer debilitating symptoms and there is now evidence that those with lower FFM also have worse symptom scores in standard COPDrelated quality of life assessment tools, even when compared with COPD patients who have lost fat mass but not FFM [5]. 4) Finally, low body weight has been identified previously as a poor prognostic indicator of survival in COPD [10,11], but a recent retrospective analysis of 142 COPD patients showed that mid-thigh muscle cross-sectional area was a better indicator of prognosis than body mass index [12]. This latter finding reinforces the concept that loss of FFM and in particular muscle mass is a common feature of COPD which has important implications for physical function, health status and survival.Despite increasing interest in skeletal muscle wasting in COPD, the underlying mechanisms remain unclear. Exercisebased pulmonary rehabilitation programmes have been shown to improve muscle function and exercise tolerance for many affected individuals. The success of exercise therapy suggests that deconditioning due to reduced physical activity plays a major role in COPD-related skeletal muscle dysfunction, but it also seems likely that other cata...

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“…Of the proteolytic pathways, the lysosomal (cathepsins) and the calcium-dependent cysteine proteases (calpains) contribute between 15 and 20% of total protein breakdown in muscles (Lecker et al, 1999). Muscle wasting in starvation (Wing and Goldberg, 1993), sepsis (Tiao et al, 1994), metabolic acidosis (Mitch et al, 1994), weightlessness (Taillandier et al, 1996), severe trauma (Biolo et al, 2000), denervation atrophy (Medina et al, 1995) and cancer cachexia, in both mice (Lorite et al, 1998) and humans (Williams et al, 1999) has been attributed to upregulation of ATP -ubiquitindependent proteolysis (ubiquitin -proteasome). In this process, proteins are tagged for degradation by the attachment of a polyubiquitin chain, which is recognised by the 26S proteasome, a large multisubunit catalytic complex.…”

mentioning

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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Contribution of the ubiquitin-proteasome pathway to overall muscle proteolysis in hypercatabolic patients

Cited by 39 publications

References 7 publications

Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis

Effect of heart failure on the regulation of skeletal muscle protein synthesis, breakdown, and apoptosis

Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease

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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