Novel aspects on the regulation of muscle wasting in sepsis

Hasselgren, Per-Olof; Menconi, Michael J.; Fareed, Moin U.; Yang, Hongmei; Wei, Wei; Evenson, Amy

doi:10.1016/j.biocel.2005.01.017

Cited by 73 publications

(59 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The present review adds to previous information by focusing mainly on the calpain system in sepsis-induced muscle wasting and by discussing some of the controversy that exists with regards to the relative importance of calpain-and caspase-dependent proteolysis in catabolic conditions. It also highlights pertinent recent reports on the role of calcium and calpains (4,6,15,25,33,75,83,89,92,99,104,111) published after our previous review (49). Other aspects of the regulation of muscle mass during sepsis, including the role of transcription factors and nuclear cofactors and the influence of posttranslational modifications of these regulators, were reviewed recently (45,46,49).…”

mentioning

confidence: 94%

“…Although calpains may be activated secondary to cell injury and calcium leak, there is increasing evidence that calpain activity is also regulated by physiological and pathophysiological mechanisms in intact cells (39). Certain aspects of the role of calpains in muscle wasting were discussed recently by others (9,22) and in a review from our laboratory (49). The present review adds to previous information by focusing mainly on the calpain system in sepsis-induced muscle wasting and by discussing some of the controversy that exists with regards to the relative importance of calpain-and caspase-dependent proteolysis in catabolic conditions.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Calpain activity and muscle wasting in sepsis

Smith¹,

Lecker²,

Hasselgren³

2008

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

105

View full text Add to dashboard Cite

Smith IJ, Lecker SH, Hasselgren PO. Calpain activity and muscle wasting in sepsis. Am J Physiol Endocrinol Metab 295: E762-E771, 2008. First published May 20, 2008 doi:10.1152/ajpendo.90226.2008.-Muscle wasting in sepsis reflects activation of multiple proteolytic mechanisms, including lyosomal and ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that activation of the calpain system also plays an important role in sepsis-induced muscle wasting. Perhaps the most important consequence of calpain activation in skeletal muscle during sepsis is disruption of the sarcomere, allowing for the release of myofilaments (including actin and myosin) that are subsequently ubiquitinated and degraded by the 26S proteasome. Other important consequences of calpain activation that may contribute to muscle wasting during sepsis include degradation of certain transcription factors and nuclear cofactors, activation of the 26S proteasome, and inhibition of Akt activity, allowing for downstream activation of Foxo transcription factors and GSK-3␤. The role of calpain activation in sepsis-induced muscle wasting suggests that the calpain system may be a therapeutic target in the prevention and treatment of muscle wasting during sepsis. Furthermore, because calpain activation may also be involved in muscle wasting caused by other conditions, including different muscular dystrophies and cancer, calpain inhibitors may be beneficial not only in the treatment of sepsis-induced muscle wasting but in other conditions causing muscle atrophy as well. muscle proteolysis; calcium; atrophy; calpastatin LOSS OF MUSCLE MASS IS COMMONLY seen in patients with sepsis (44, 55). Several other catabolic conditions, such as burn injury, cancer, uremia, and AIDS, are also associated with muscle wasting (20,27,29,79). Muscle wasting has several significant clinical consequences. For example, loss of muscle mass results in weakness and fatigue, in turn resulting in delayed ambulation and prolonged rehabilitation. When patients are bedridden for long periods of time, the risks for thromboembolic events as well as for pneumonia and other pulmonary complications increase. Prolonged bed rest in itself causes loss of muscle mass, thus creating a vicious cycle (35). Patients treated in the intensive care unit may need ventilatory support for extended periods of time when respiratory muscles are atrophying (82).Under normal conditions, muscle mass is maintained by a balance between protein synthesis and degradation, and muscle wasting can occur in any situation when this equilibrium is perturbed. There is evidence that loss of muscle mass during sepsis to a great extent reflects activated breakdown of muscle proteins, in particular the contractile proteins actin and myosin (48), but reduced protein synthesis may also contribute to sepsis-induced muscle wasting (62).Although increased expression and activity of the ubiquitinproteasome proteolytic pathway, including a dramatic upregulation of the muscle-specific ubiquitin ligases atrogin-1 and M...

show abstract

mentioning

confidence: 94%

mentioning

confidence: 99%

Calpain activity and muscle wasting in sepsis

Smith¹,

Lecker²,

Hasselgren³

2008

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

105

View full text Add to dashboard Cite

show abstract

“…Muscle wasting occurs within many life-threatening diseases such as cancer (termed cancer cachexia) [1], AIDS [2], Sepsis [3], heart failure [4] and ageing (sarcopenia) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Impaired hypertrophy in myoblasts is improved with testosterone administration

Deane

Hughes

Sculthorpe

et al. 2013

The Journal of Steroid Biochemistry and Molecular Biology

View full text Add to dashboard Cite

“…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).…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Novel aspects on the regulation of muscle wasting in sepsis

Cited by 73 publications

References 89 publications

Calpain activity and muscle wasting in sepsis

Calpain activity and muscle wasting in sepsis

Impaired hypertrophy in myoblasts is improved with testosterone administration

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

Contact Info

Product

Resources

About

Novel aspects on the regulation of muscle wasting in sepsis

Cited by 73 publications

References 89 publications

Calpain activity and muscle wasting in sepsis

Calpain activity and muscle wasting in sepsis

Impaired hypertrophy in myoblasts is improved with testosterone administration

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

Contact Info

Product

Resources

About

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