Ischemia and reperfusion of skeletal muscle lead to the  appearance of a stable lipid free radical in the circulation

Both ischemia and reperfusion injury and contractile activity are associated with the generation of reactive oxygen species and free radicals by skeletal muscle. In addition, exercise has been reported to lead to the formation of a circulating free radical species that is detectable in the blood by spin trapping before analysis by electron-spin resonance (ESR) techniques. Previous analysis of the ESR signal indicated that the circulating species is either a carbon- or oxygen-centered lipid-derived free radical. The current data indicate that this species is present in the blood of anesthetized rats after 4-h ischemia and 1 h of reperfusion of a single hindlimb. During 4 h of ischemia, the species was also present in microdialysates from the tibialis anterior muscle but was unchanged in magnitude compared with control tissue. During 1 h of reperfusion, the signal intensity increased by a mean of 420% ( P < 0.05, n = 4). Hydroxyl radical activity in the interstitial fluid also significantly increased during ischemia and further increased by a mean of 210% ( P < 0.05, n = 4) during reperfusion. No changes in interstitial superoxide levels were seen, but interstitial PGE2 content also increased during reperfusion. A significant positive correlation was found between the magnitude of the ESR signal and both the hydroxyl radical activity and PGE2 content of microdialysis fluids. These data support the hypothesis that the circulating free radical species is formed in the interstitial fluid by hydroxyl radical interaction with a lipid that may be released from reperfused tissue with a similar pattern to prostanoids.

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Contractile activity-induced oxidative stress: cellular origin and adaptive responses

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c621 ◽

2001 ◽

Vol 280 (3) ◽

pp. C621-C627 ◽

Cited By ~ 212

Author(s):

A. McArdle ◽

D. Pattwell ◽

A. Vasilaki ◽

R. D. Griffiths ◽

M. J. Jackson

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Free Radical ◽

Muscle Protein ◽

Contractile Activity ◽

Cellular Damage ◽

Radical Species ◽

Free Radical Species ◽

Short Period

Previous studies have reported that oxidizing free radical species are generated during exercise, and there has been considerable interest in the potential effects of these on exercising tissues. We hypothesized that contracting skeletal muscle was a major source of oxidizing free radical species and that untrained skeletal muscle would adapt to the oxidative stress of a single short period of contractile activity by upregulation of the activity of cytoprotective proteins in the absence of overt cellular damage. Fifteen minutes of aerobic contractile activity was found to induce a rapid release of superoxide anions from mouse skeletal muscle in vivo, and studies with contracting cultured skeletal muscle myotubes confirmed that this was due to release from myocytes rather than other cell types present within muscle tissue in vivo. This increased oxidant production caused a rapid, transient reduction in muscle protein thiol content, followed by increases in the activities of superoxide dismutase and catalase and in content of heat shock proteins. These changes occurred in the absence of overt damage to the muscle cells.

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Free radical-mediated skeletal muscle dysfunction in inflammatory conditions

Journal of Applied Physiology ◽

10.1152/japplphysiol.01138.2006 ◽

2007 ◽

Vol 102 (5) ◽

pp. 2056-2063 ◽

Cited By ~ 92

Author(s):

Gerald S. Supinski ◽

Leigh A. Callahan

Keyword(s):

Skeletal Muscle ◽

Free Radicals ◽

Free Radical ◽

Muscle Weakness ◽

Muscle Function ◽

Muscle Dysfunction ◽

Radical Species ◽

Inflammatory Conditions ◽

Skeletal Muscle Dysfunction ◽

Free Radical Species

Loss of functional capacity of skeletal muscle is a major cause of morbidity in patients with a number of acute and chronic clinical disorders, including sepsis, chronic obstructive pulmonary disease, heart failure, uremia, and cancer. Weakness in these patients can manifest as either severe limb muscle weakness (even to the point of virtual paralysis), respiratory muscle weakness requiring mechanical ventilatory support, and/or some combination of these phenomena. While factors such as nutritional deficiency and disuse may contribute to the development of muscle weakness in these conditions, systemic inflammation may be the major factor producing skeletal muscle dysfunction in these disorders. Importantly, studies conducted over the past 15 years indicate that free radical species (superoxide, hydroxyl radicals, nitric oxide, peroxynitrite, and the free radical-derived product hydrogen peroxide) play an key role in modulating inflammation and/or infection-induced alterations in skeletal muscle function. Substantial evidence exists indicating that several free radical species can directly alter contractile protein function, and evidence suggests that free radicals also have important effects on sarcoplasmic reticulum function, on mitochondrial function, and on sarcolemmal integrity. Free radicals also modulate activation of several proteolytic pathways, including proteosomally mediated protein degradation and, at least theoretically, may also influence pathways of protein synthesis. As a result, free radicals appear to play an important role in regulating a number of downstream processes that collectively act to impair muscle function and lead to reductions in muscle strength and mass in inflammatory conditions.

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Effect of the Extract from Salvia Miltiorrhiza Radix (SMR) on Skeletal Muscle Ischemia and Reperfusion Injury in Rabbits

Canadian Journal of Plastic Surgery ◽

10.1177/229255039700500302 ◽

1997 ◽

Vol 5 (3) ◽

pp. 171-175

Author(s):

Daping Yang ◽

Steven F Frcsc

Keyword(s):

Skeletal Muscle ◽

Hydroxyl Radical ◽

Reperfusion Injury ◽

Salvia Miltiorrhiza ◽

Treated Group ◽

Ultrastructural Changes ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Danshen Injection ◽

Muscle Ischemia

The extract of salvia miltiorrhiza radix (SMR) is a well known Chinese herbal medicine known as danshen. It has been found in several experimental studies, published mostly in China, to have antioxidant properties. The purpose of this experiment was, therefore, to compare the effects of danshen injection with those of superoxide dismutase (SOD) and mannitol on skeletal muscle ischemia and reperfusion injury in rabbits. The authors used a rabbit limb replantation model subjected to 5 h of global ischemia. Immediately before reperfusion, the animals received SOD (16,000 U/kg), mannitol (1 g/kg) or danshen injection (2 g/kg) intravenously. Both danshen and mannitol significantly increased limb survival (P<0.01). Increased limb survival was observed in the SOD-treated group compared with the saline-treated group (P<0.05) but not with the ischemic group (P>0.05). Light and transmission electron microscopy revealed that the pathologic and ultrastructural changes in skeletal muscles, which were subjected to 5 h of ischemia followed by 2 h of reperfusion, were reduced with SOD, mannitol and danshen injection. These results suggest that the hydroxyl radical seems to be the most important factor in ischemia and reperfusion injury to skeletal muscle and that danshen, like mannitol, may have a role in antioxidation as a hydroxyl radical scavenger.

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