Calpain activity and muscle wasting in sepsis

1 Department of Surgery and 2 Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Submitted 11 February 2008 ; accepted in final form 13 May 2008 ABSTRACT Muscle wasting in sepsis reflects activation of multiple proteolytic mechanisms, including lyo...

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Published in:American journal of physiology: endocrinology and metabolism 2008-10, Vol.295 (4), p.E762-E771
Main Authors: Smith, Ira J, Lecker, Stewart H, Hasselgren, Per-Olof
Format: Article
Language:English
Subjects:
Animals
Calcium
Calcium - metabolism
Calpain - antagonists & inhibitors
Calpain - genetics
Calpain - physiology
Humans
Muscle, Skeletal - pathology
Muscle, Skeletal - physiopathology
Musculoskeletal system
Proteases
Proteins
Proto-Oncogene Proteins c-akt - physiology
Reviews
Sarcomeres - physiology
Sepsis
Sepsis - complications
Sepsis - drug therapy
Sepsis - pathology
Transcription Factors
Wasting Syndrome - drug therapy
Wasting Syndrome - etiology
Wasting Syndrome - pathology
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Summary:1 Department of Surgery and 2 Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Submitted 11 February 2008 ; accepted in final form 13 May 2008 ABSTRACT 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-3β. 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 Address for reprint requests and other correspondence: P.-O. Hasselgren, Dept. of Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Ave. ST919, Boston, MA (e-mail: phasselg{at}bidmc.harvard.edu )
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.90226.2008