Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis

Hobler, Scott C.; Williams, Arthur R.; Fischer, David; Wang, Jing Jing; Sun, Xiaoyan; Fischer, Josef E.; Monaco, John J.; Hasselgren, Per-Olof

doi:10.1152/ajpregu.1999.277.2.r434

Cited by 66 publications

(78 citation statements)

References 31 publications

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“…In septic rats, Voisin et al (749) first observed a rise in mRNA for E2-14k, an E2 protein that mediates ubiquitin conjugation via the N-end rule pathway. Potential involvement of E2-14k was reinforced by data from Hobler et al (316) who observed that E2-14k mRNA was elevated in fast-twitch (but not slow-twitch) muscle of septic rats. Later studies confirmed upregulation of E2-14k in fasttwitch muscles of rats subjected to cecal ligation and puncture (200) or endotoxemia (113).…”

Section: A the Ubiquitin-proteasome Pathway In Critical Illnessmentioning

confidence: 94%

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The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

292

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Section: A the Ubiquitin-proteasome Pathway In Critical Illnessmentioning

confidence: 94%

“…Voisin et al (749) demonstrated that mRNA for subunits of the proteasome fluctuate in parallel with muscle proteolysis rates. Proteolytic activity of the proteasome is elevated by experimental sepsis (316), a response that involves both trypsin-and chymotrypsin-like peptidase activities (486).…”

Section: A the Ubiquitin-proteasome Pathway In Critical Illnessmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

292

329

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“…The maintenance of Ub homeostasis is essential for cell viability, and an adequate supply of Ub is crucial for the ability of the cell to withstand stress (1)(2)(3). Under such conditions, aberrant proteins are formed in large amounts, leading to an increase in the activity of the Ub-proteasome system (UPS), which partially results from accelerated rate of synthesis of Ub and other components of the UPS (4)(5)(6). Interestingly, the total amount and ratio between free and bound Ub vary among different tissues under basal conditions (7), and significant changes occur in Ub homeostasis during different pathologies (4,8).…”

mentioning

confidence: 99%

“…Under such conditions, aberrant proteins are formed in large amounts, leading to an increase in the activity of the Ub-proteasome system (UPS), which partially results from accelerated rate of synthesis of Ub and other components of the UPS (4)(5)(6). Interestingly, the total amount and ratio between free and bound Ub vary among different tissues under basal conditions (7), and significant changes occur in Ub homeostasis during different pathologies (4,8). The mechanisms that underlie Ub regulation under different pathophysiological conditions are largely unknown.…”

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confidence: 99%

Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation

Shabek

Herman-Bachinsky

Ciechanover

2009

Proc. Natl. Acad. Sci. U.S.A.

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The mechanisms that regulate the ubiquitin (Ub)-proteasome system's own components, although critically important, are largely unknown. Ub, a principal component of the system, must be maintained at adequate levels to support cellular homeostasis under basal and stressed conditions. It was suggested that Ub is degraded as part of the polyubiquitin chain along with its substrate. Here, we demonstrate in a direct manner that Ub is indeed degraded in a ''piggyback'' mechanism. Also, it has been shown that monomeric Ub can be rapidly degraded when a C-terminal tail of a minimal length is fused to it. The tail, which may represent the substrate or part of it, or a naturally occurring extended form of Ub, probably allows entry of the protein into the 20S catalytic chamber, while Ub serves as an anchor to the 19S complex. Here, we show that shorter-tailed Ubs, such as UBB ؉1 , bind to the proteasome but because they cannot be efficiently degraded, they inhibit the degradation of other Ub system's substrates such as Myc, p21, Mdm2, and MyoD. The inhibition depends on the ability of the tailed Ubs to be ubiquitinated: their mere binding to the proteasome is not sufficient. Interestingly, the inhibition affects only substrates that must undergo ubiquitination for their degradation: ornithine decarboxylase that is targeted by the proteasome in a Ub-independent manner, is not affected by the short-tailed ubiquitinated Ubs, suggesting it binds to the 19S complex in a site different from that to which ubiquitinated substrates bind.UBB ϩ1 ͉ neurodegeneration ͉ extended ubiquitin ͉ proteasomal recognition

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“…This experimental model was used because we (49,76) and others (29) found previously that treatment of cultured myotubes with dexamethasone resulted in increased calpain-and ubiquitin-proteasome-dependent proteolysis, similar to the situation observed in muscle wasting caused by sepsis (14,28,72,77). Cytosolic calcium concentrations were determined by fura-2 AM fluorescence, and SOCE was measured by using calcium "add-back" to muscle cells after depletion of calcium stores.…”

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confidence: 99%

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

Itagaki

Menconi

Antoniu

et al. 2010

American Journal of Physiology-Cell Physiology

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Hasselgren PO. Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A 2-dependent mechanism. Am J Physiol Cell Physiol 298: C1127-C1139, 2010. First published January 27, 2010; doi:10.1152/ajpcell.00309.2009.-Muscle wasting in various catabolic conditions is at least in part regulated by glucocorticoids. Increased calcium levels have been reported in atrophying muscle. Mechanisms regulating calcium homeostasis in muscle wasting, in particular the role of glucocorticoids, are poorly understood. Here we tested the hypothesis that glucocorticoids increase intracellular calcium concentrations in skeletal muscle and stimulate storeoperated calcium entry (SOCE) and that these effects of glucocorticoids may at least in part be responsible for glucocorticoid-induced protein degradation. Treatment of cultured myotubes with dexamethasone, a frequently used in vitro model of muscle wasting, resulted in increased intracellular calcium concentrations determined by fura-2 AM fluorescence measurements. When SOCE was measured by using calcium "add-back" to muscle cells after depletion of intracellular calcium stores, results showed that SOCE was increased 15-25% by dexamethasone and that this response to dexamethasone was inhibited by the store-operated calcium channel blocker BTP2. Dexamethasone treatment stimulated the activity of calcium-independent phospholipase A 2 (iPLA2), and dexamethasone-induced increase in SOCE was reduced by the iPLA 2 inhibitor bromoenol lactone (BEL). In additional experiments, treatment of myotubes with the store-operated calcium channel inhibitor gadolinium ion or BEL reduced dexamethasone-induced increase in protein degradation. Taken together, the results suggest that glucocorticoids increase calcium concentrations in myocytes and stimulate iPLA 2-dependent SOCE and that glucocorticoid-induced muscle protein degradation may at least in part be regulated by increased iPLA 2 activity, SOCE, and cellular calcium levels. glucocorticoids; muscle; wasting MUSCLE WASTING, mainly reflecting stimulated degradation of myofibrillar proteins, is commonly seen in patients with sepsis, severe injury, and cancer (24, 52). Loss of muscle mass also occurs in patients with muscular dystrophy (30, 31). In previous studies, we found evidence (4, 15, 79) that sepsis-induced muscle proteolysis was associated with increased uptake and tissue levels of calcium in skeletal muscle. Additional reports suggest that muscle atrophy caused by other catabolic conditions, including denervation, burn injury, and muscular dystrophy, is also associated with increased tissue concentrations of calcium (2,3,10,17,64,73). These observations are significant because calcium is an important regulator of muscle protein balance and may link systemic catabolic responses to stimulated protein breakdown in skeletal muscle (16,34,50). The mechanisms regulating calcium entry and cellular levels of calcium in muscle-wasting conditions are not known.Glucocorticoids are prom...

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Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis

Cited by 66 publications

References 31 publications

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism

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Activity and expression of the 20S proteasome are increased in skeletal muscle during sepsis

Cited by 66 publications

References 31 publications

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Ubiquitin degradation with its substrate, or as a monomer in a ubiquitination-independent mode, provides clues to proteasome regulation

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A2-dependent mechanism

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Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A₂-dependent mechanism