Role of Calcium-Activated Neutral Protease (Calpain) With Diet and Exercise

Belcastro, A. N.; Albisser, T. A.; Littlejohn, Brent

doi:10.1139/h96-029

Cited by 31 publications

(27 citation statements)

References 53 publications

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“…Early studies provided evidence that release of myofilaments from the sarcomere occurs in various catabolic conditions, including fasting and treatment with glucocorticoids (24) and that calcium/calpain-dependent mechanisms may be involved (10,30). Skeletal muscle contractile proteins, actin and myosin, are poor calpain substrates but other proteins that are important for the structural integrity of the sarcomere are excellent calpain substrates.…”

Section: Calpain Activation Disrupts the Sarcomere And Releases Myofimentioning

confidence: 99%

Calpain activity and muscle wasting in sepsis

Smith¹,

Lecker²,

Hasselgren³

2008

American Journal of Physiology-Endocrinology and Metabolism

108

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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...

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Section: Calpain Activation Disrupts the Sarcomere And Releases Myofimentioning

confidence: 99%

Calpain activity and muscle wasting in sepsis

Smith¹,

Lecker²,

Hasselgren³

2008

American Journal of Physiology-Endocrinology and Metabolism

108

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“…During muscle excitation, the influx of Ca 2+ is markedly increased, leading to a progressive intracellular accmulation of Ca 2+ both in vitro (Bianchi & Shanes, 1959; Curtis, 1966; Gissel & Clausen, 1999, 2000) and in vivo (Sreter et al 1980; Everts et al 1993). Ca 2+ may enter normal, contracting muscle cells through voltage gated Na + channels, through voltage gated L‐type Ca 2+ channels (Gissel & Clausen, 1999, 2001) and through stretch‐activated channels (Belcastro et al 1996; McBride et al 2000). Store‐operated Ca 2+ uptake may occur through the transient receptor potential (TRP) channels which can also function as Ca 2+ influx channels in skeletal muscle (Kurebayashi & Ogawa, 2001; Vandebrouck et al 2002).…”

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confidence: 99%

Excitation‐induced Ca²⁺ influx and muscle damage in the rat: loss of membrane integrity and impaired force recovery

Mikkelsen

Fredsted

Gissel

et al. 2004

The Journal of Physiology

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Prolonged or unaccustomed exercise leads to loss of contractility and muscle cell damage. The possible role of an increased uptake of Ca 2+ in this was explored by examining how graded fatiguing stimulation, leading to a graded uptake of Ca 2+ , results in progressive loss of force, impairment of force recovery, and loss of cellular integrity. The latter is indicated by increased [14 C]sucrose space and lactic acid dehydrogenase (LDH) release. Isolated rat extensor digitorum longus (EDL) muscles were allowed to contract isometrically using a fatiguing protocol with intermittent stimulation at 40 Hz. Force declined rapidly, reaching 11% of the initial level after 10 min and stayed low for up to 60 min. During the initial phase (2 min) of stimulation 45 Ca uptake showed a 10-fold increase, followed by a 4-to 5-fold increase during the remaining period of stimulation. As the duration of stimulation increased, the muscles subsequently regained gradually less of their initial force. Following 30 or 60 min of stimulation, resting 45 Ca uptake, [ 14 C]sucrose space, and LDH release were increased 4-to 7-fold, 1.4-to 1.7-fold and 3-to 9-fold, respectively (P < 0.001). The contents of Ca 2+ and Na + were also increased (P < 0.01), a further indication of loss of cellular integrity. When fatigued at low [Ca 2+ ] o (0.65 mM), force recovery was on average twofold higher than that of muscles fatigued at high [Ca 2+ ] o (2.54 mM). Muscles showing the best force recovery also had a 41% lower total cellular Ca 2+ content (P < 0.01). In conclusion, fatiguing stimulation leads to a progressive functional impairment and loss of plasma membrane integrity which seem to be related to an excitation-induced uptake of Ca 2+ . Mechanical strain on the muscle fibres does not seem a likely mechanism since very little force was developed beyond 10 min of stimulation. Intense exercise, such as extended periods of running, strength training, sprinting or eccentric exercise, disrupts the normal ultrastructure of skeletal muscle (Waterman-Storer, 1991;Belcastro, 1993;Belcastro et al. 1998). Impaired force recovery seen after intense exercise can be due to structural damage such as myofibrillar and cytoskeletal disruptions often leading to Z-disc streaming (Hoppeler, 1986; WatermanStorer, 1991;Appell et al. 1992;Gibala et al. 1995), as well as disturbances to mitochondria and the SR-T-tubular system (Hoppeler, 1986;Gibala et al. 1995). Loss of sarcolemmal integrity has also repeatedly been reported after prolonged or unaccustomed exercise (e.g. Stupka et al. 2001;Clarkson & Hubal, 2002), contributing to the functional impairment.Several mechanisms have been proposed to explain the functional impairment and it is unlikely to be caused by one single factor. The causes of functional impairment could be either mechanical damage due to eccentric contractions (Armstrong, 1986(Armstrong, , 1990, loss of excitability (Nielsen & Overgaard, 1996;Clausen, 1996;Overgaard et al. 1999;Carlsen & Villarin, 2002), or Ca 2+ -induced damage (Gissel & Cl...

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“…Evidence for Z‐band disruption and release of myofilaments in skeletal muscle has been reported previously in certain catabolic conditions, including fasting and treatment with glucocorticoids (12). There is evidence that release of myofilaments from the myofibrils reflects calcium‐dependent calpain activity (13–15). The influence of sepsis on Z‐band integrity and release of myofilaments is not known.…”

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confidence: 99%

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism

et al. 1999

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Sepsis is associated with a pronounced catabolic response in skeletal muscle, mainly reflecting degradation of the myofibrillar proteins actin and myosin. Recent studies suggest that sepsis-induced muscle proteolysis may reflect ubiquitin-proteasome-dependent protein breakdown. An apparently conflicting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils. Thus, it is possible that actin and myosin need to be released from the myofibrils before they can be ubiquitinated and degraded by the proteasome. We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent release of myofilaments in skeletal muscle. Sepsis induced in rats by cecal ligation and puncture resulted in increased gene expression of micro-calpain, m-calpain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle. The release of myofilaments from myofibrillar proteins was increased in septic muscle. This response to sepsis was blocked by treating the rats with dantrolene, a substance that inhibits the release of calcium from intracellular stores to the cytoplasm. The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependent release of myofilaments in skeletal muscle. Release of myofilaments may be an initial and perhaps rate-limiting component of sepsis-induced muscle breakdown.

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Role of Calcium-Activated Neutral Protease (Calpain) With Diet and Exercise

Cited by 31 publications

References 53 publications

Calpain activity and muscle wasting in sepsis

Calpain activity and muscle wasting in sepsis

Excitation‐induced Ca²⁺ influx and muscle damage in the rat: loss of membrane integrity and impaired force recovery

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism

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Role of Calcium-Activated Neutral Protease (Calpain) With Diet and Exercise

Cited by 31 publications

References 53 publications

Calpain activity and muscle wasting in sepsis

Calpain activity and muscle wasting in sepsis

Excitation‐induced Ca2+ influx and muscle damage in the rat: loss of membrane integrity and impaired force recovery

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism

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Excitation‐induced Ca²⁺ influx and muscle damage in the rat: loss of membrane integrity and impaired force recovery