Oxidative Stress In Skeletal Muscle Research Articles

Alpha-lipoic Acid Attenuates Exercise-induced Oxidative Stress And Enhances Heat Shock Protein Responses

Uncontrolled oxidative stress, a state where the increased production of ROS overwhelms endogenous antioxidant protection, may result in macromolecular damage and perturbation of redox control of signalling and cellular events. The heat shock proteins (HSPs) respond to a wide variety of stress, including oxidative stress. HSPs function primarily as molecular chaperones, but also control protein synthesis and trafficking, as well as regulate cellular adaptation and survival. PURPOSE: Several antioxidant supplementation strategies have been used to cope with exercise-induced oxidative stress and to facilitate adaptations to exercise. While antioxidant supplementation diminishes exercise-induced oxidative stress, there is also a risk of decreasing the normal response of tissues to exercise and blunting the adaptations. In this study we examined the protective role of natural thiol antioxidant, alpha-lipoic acid (LA) supplementation at rest, after exercise and at different recovery points in skeletal muscle in horses. METHODS: Six standardbred trotters were examined on the treadmill and exercised 75 min at individually defined aerobic level. Blood and muscle biopsy samples were taken before and immediately after treadmill exercise, as well as after 2-, 6-, 24- and 48-hour recovery. RESULTS: LA supplementation (25 mg kg-1 day-1) for five weeks increased the resting levels of HSP90 and the recovery levels of inducible HSP70 in gluteus medius muscle. In addition, following LA-supplementation, we observed a significant decrease in exercise-induced protein oxidation in plasma and free radical formation in muscle, measured by EPR signals. CONCLUSION: Our findings suggest that LA enhances HSP levels and decreases exercise-induced oxidative stress in skeletal muscle.

Chronic Left‐Ventricular Dysfunction Increases Oxidative Stress in Skeletal Muscle: Potential Mechanism of Cardiac Cachexia

Skeletal muscle (SM) atrophy during congestive heart failure is a process associated with a poor prognosis whose pathogenesis remains poorly understood. To determine if there is an increase in oxidative stress in SM atrophy induced by congestive heart failure, we used a murine model of chronic left‐ventricular dysfunction (CLVD) provoked by myocardial infarction. The left coronary artery was ligated in 8‐12 week old FVB mice (LAD, n=7) and sham‐operated mice were used as controls (ctr, n=12). LAD‐ligated mice had significant left‐ventricular dysfunction at 12 weeks by echocardiography (% FS, ctr, 47.24 ± 4.4% vs. LAD, 28.6 ± 4.7%; p<0.05, LVDs, ctr, 4.4 ± 0.4mm vs. LAD, 3.6 ± 0.1mm, p<0.01; LVDd, control 1.9 ± 0.1mm vs. LAD, 3.1 ± 0.5mm, p<0.01). In addition, LAD ligation produced significant SM atrophy as evidenced by a reduced body weight (ctr, 29.61 ± 0.37g vs. LAD, 27.76 ± 0.68g, p<0.05), SM weight (gastrocnemius, GM) (ctr, 133.9 ± 2.2mg vs. LAD, 126.3 ± 1.7mg, p<0.05), GM fiber cross‐sectional area (control 1292.2 ± 70.1 μm2, n=5, vs. LAD, 934.1 ± 10.7 μm2, n=2, p<0.05), and a significant shift in the myofiber size distribution towards smaller size fibers (p<0.01). SM wasting was associated with a 51% increase in muscle superoxide levels as quantified by staining GM cross‐sections with superoxide‐sensitive dye dihydroethidium (relative DHE fluorescence, ctr, 18.20 ± 2.9 vs. LAD, 27.40 ± 5.4, p<0.05). In summary, CLVD produces an increase in oxidative stress that is associated with progressive muscle atrophy.

Direct Renin Inhibition Improves Systemic Insulin Resistance and Skeletal Muscle Glucose Transport in a Transgenic Rodent Model of Tissue Renin Overexpression

Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6-9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg . d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT(1)R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT(1)R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT(1)R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT(1)R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.

α-Lipoic acid modulates thiol antioxidant defences and attenuates exercise-induced oxidative stress in standardbred trotters

Several micronutrient supplementation strategies are used to cope with oxidative stress, although their benefits have recently been questioned. The aim of the present study was to examine the effects of DL-α-lipoic acid (LA) in response to acute exercise and during recovery in horses. Six standardbred trotters were tested on the treadmill before and after 5-week LA supplementation (25 mg/kg body weight/day). According to electron paramagnetic resonance measurements, strenuous aerobic exercise increased significantly free radical formation in the gluteus medius muscle, which was prevented by LA supplementation. The activities of thioredoxin reductase and glutathione reductase in muscle were significantly increased in LA-treated horses, but neither LA nor exercise affected muscle thioredoxin activity. LA increased the concentration of total glutathione in muscle at rest and during recovery. Treatment with LA blunted the exercise-induced increase in plasma oxygen radical absorbance capacity and decreased the post-exercise levels of lipid hydroperoxides in plasma and malondialdehyde in plasma and in muscle. These findings suggest that LA enhances thiol antioxidant defences and decreases exercise-induced oxidative stress in skeletal muscle.

Human Skeletal Muscle Aging and the Oxidative System: Cellular Events

As we age, the aerobic and functional capacities of our major physiological systems progressively decline. In the case of the neuromuscular system, reductions in strength and mobility cause a deterioration in motor performance and in turn a greater tendency to fall (with increased risk of fractures), impaired mobility, disability and loss of independence in the elderly. Given the increase in our life expectancy and the consequent growth in the elderly population, these conditions will have an increasing impact on modern healthcare systems, and their prevention and attenuation needs to be addressed. Several intervention strategies have been used to improve motor performance among the aging. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS) generated by the addition of a single electron to the oxygen molecule As the level of oxidative stress in skeletal muscle increases with age, the production of some antioxidant enzymes increases adaptively to compensate in part. The aging process is characterized by an imbalance between an increase in the production of reactive oxygen species in the organism and the antioxidant defences as a whole. The goal of this review is to examine the results of existing studies on oxidative stress in aging human skeletal muscles, taking into account different physiological factors (sex, fiber composition, muscle type and function).

Effect of T 3 on metabolic response and oxidative stress in skeletal muscle from sedentary and trained rats

We investigated whether swim training modifies the effect of T 3-induced hyperthyroidism on metabolism and oxidative damage in rat muscle. Respiratory capacities, oxidative damage, levels of antioxidants, and susceptibility to oxidative challenge of homogenates were determined. Mitochondrial respiratory capacities, H 2O 2 release rates, and oxidative damage were also evaluated. T 3-treated rats exhibited increases in muscle respiratory capacity, which were associated with enhancements in mitochondrial respiratory capacity and tissue mitochondrial protein content in sedentary and trained animals, respectively. Hormonal treatment induced muscle oxidative damage and GSH depletion. Both effects were reduced by training, which also attenuated tissue susceptibility to oxidative challenge. The changes in single antioxidant levels were slightly related to oxidative damage extent, but the examination of parameters affecting the susceptibility to oxidants indicated that training was associated with greater effectiveness of the muscle antioxidant system. Training also attenuated T 3-induced increases in H 2O 2 production and, therefore, oxidative damage of mitochondria by lowering their content of autoxidizable electron carriers. The above results suggest that moderate training is able to reduce hyperthyroid state-linked tissue oxidative damage, increasing antioxidant protection and decreasing the ROS flow from the mitochondria to the cytoplasmic compartment.

Adiponectin upregulates ferritin heavy chain in skeletal muscle cells.

OBJECTIVE—Adiponectin is an adipocyte-derived protein that acts to reduce insulin resistance in the liver and muscle and also inhibits atherosclerosis. Although adiponectin reportedly enhances AMP-activated protein kinase and inhibits tumor necrosis factor-α action downstream from the adiponectin signal, the precise physiological mechanisms by which adiponectin acts on skeletal muscles remain unknown.RESEARCH DESIGN AND METHODS—We treated murine primary skeletal muscle cells with recombinant full-length human adiponectin for 12 h and searched, using two-dimensional electrophoresis, for proteins upregulated more than threefold by adiponectin compared with untreated cells.RESULTS—We found one protein that was increased 6.3-fold with adiponectin incubation. MALDI-TOF (matrix-assisted laser desorption/ionization−top of flight) mass spectrometric analysis identified this protein as ferritin heavy chain (FHC). When murine primary skeletal muscle cells were treated with adiponectin, IκB-α phosphorylation was observed, suggesting that adiponectin stimulates nuclear factor (NF)-κB activity. In addition, FHC upregulation by adiponectin was inhibited by NF-κB inhibitors. These results suggest NF-κB activation to be involved in FHC upregulation by adiponectin. Other NF-κB target genes, manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS), were also increased by adiponectin treatment. We performed a reactive oxygen species (ROS) assay using CM-H2DCFDA fluorescence and found that ROS-reducing effects of adiponectin were abrogated by FHC or MnSOD small-interfering RNA induction.CONCLUSIONS—We have demonstrated that adiponectin upregulates FHC in murine skeletal muscle tissues, suggesting that FHC elevation might partially explain how adiponectin protects against oxidative stress in skeletal muscles.

371 POSTER Toxicology and pharmacokinetics of humanized AR47A6.4.2, the first unconjugated therapeutic monoclonal antibody targeting TROP-2

Polyphenols (PP) have demonstrated beneficial effects on low-grade inflammation and oxidative stress; however, little is known about their effect on highly inflamed muscle. The purposes of this study were (i) to evaluate muscle alteration induced by high-grade inflammation, and (ii) to test the effects of red grape PP supplementation on these alterations.We used a transgenic mice model (transforming growth factor [TGF] mice) to develop a high T cell–dependent inflammation and C57 BL/6 control (CTL) mice model. Skeletal muscles of TGF and CTL mice were investigated for inflammation, atrophy and oxidative stress markers. Isolated mitochondria from hindlimb muscles were used for respiration with pyruvate as substrate and oxidative damages were measured by Western blot. TGF mice were supplemented with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk. Data were analyzed by one-way analysis of variance (ANOVA) and post hoc Bonferroni's multiple comparison tests.TGF mice presented skeletal muscle inflammation, oxidative stress, mitochondrial alteration and muscle atrophy. Atrophy was associated with two distinct pathways: (i) one linked to inflammation, NF-κB activation and increased ubiquitin ligase expression, and (ii) one dependent on reactive oxygen species (ROS) production leading to damaged mitochondria accumulation and activation of caspase-9 and 3. Supplementation of TGF mice with a mixture of red grape polyphenols (50 mg/kg/d) for 4 wk improved mitochondrial function and highly decreased caspases activation, which allowed muscle atrophy mitigation.These observations suggest that nutritional dosages of red grape polyphenols might be beneficial for reducing skeletal muscle atrophy, even in a high-grade inflammation environment.

Skeletal Muscle Capillarity during Hypoxia: VEGF and Its Activation

Long-term exposure of humans and many mammals to hypoxia leads to the activation of several cellular mechanisms within skeletal muscles that compensate for a limited availability of cellular oxygen. One of these cellular mechanisms is to increase the expression of a subset of hypoxia-inducible genes, including the expression of vascular endothelial growth factor (VEGF). The VEGF promoter contains a hypoxic response element (HRE) that can bind the transcription factor, hypoxia-inducible factor-1alpha; (HIF-1alpha), and initiate transcriptional activation of the VEGF gene. VEGF gene expression is critically important for skeletal muscle angiogenesis and VEGF gene deletion in the mouse has been shown to greatly reduce skeletal muscle capillarity. However, HIF-1alpha-dependent transcriptional activation of the VEGF gene may not be the only signaling pathway that leads to increased or maintained VEGF levels under conditions of acute or long-term hypoxia. Additional mechanisms, induced during hypoxic exposure that could signal skeletal muscle VEGF activation include inflammation, possibly linked to reactive O(2) species generation, or a change in cellular energy status as reflected by AMP kinase activity. These pathways may provide quite different mechanisms for VEGF upregulation in the context of muscular activity during long-term exposure to a hypoxic environment such as occurs at high altitude. This review will accordingly discuss the potential cellular signals or stimuli resulting from hypoxic exposure that could increase myocyte VEGF expression. These cellular signals include 1) a decrease in intracellular P(O(2)), 2) skeletal muscle inflammation, associated cytokines and oxidative stress, and 3) an increase in AMP kinase activity and adenosine accompanying a reduction in cellular energy potential.

Near Infrared Radiation Attenuates Diabetes-Induced Oxidative Damage in the Rectus Femoris Muscle

Oxidative stress and mitochondrial dysfunction are central in the pathogenesis of muscle cell death and atrophy in diabetes, obesity and aging. Low energy photon irradiation by light in the far red to near-infrared (NIR) spectral range (630-1000 nm) using low energy lasers or light emitting diode arrays has been shown to increase cell proliferation, accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured retina and optic nerve. The therapeutic effects of NIR light are believed to be triggered by the interaction of NIR light with the mitochondrial enzyme, cytochrome oxidase, and result in improved cellular mitochondrial energy metabolism, antioxidant and anti-apoptotic activity and cell survival. PURPOSE: The present study was undertaken to test the hypothesis that a brief course of NIR-LED treatment would improve mitochondrial function, attenuate oxidative stress and improve muscle function in a rodent model of type I diabetes, the streptozotocin-treated (STZ, dose 50 mg/kg) adult Wistar rat. METHODS: Animals were irradiated at 670 nm for 5 minutes at an energy density of 4 joules cm2 using a light emitting diode array (Quantum Devices, Barneveld, WI) once a day for 17 days, after which they were euthanized and the rectus femoris (RF) muscles rapidly harvested. RESULTS: Blood glucose concentrations were greater in the STZ (STZ= 23.2 ± 2.9 mM; STZ-NIR= 21.7 ± 1.9 mM) than in the control (CON= 3.8 ± 0.4 mM) rats. RF mass was significantly decreased in STZ (0.84 ± 0.08 g) and STZ-NIR (0.89 ± 0.11 g) compared to CON (1.09 ± 0.06 g) rats. The total antioxidant capacity in the RF was greater in STZ (0.07 ± 0.02 nmoles/mg) and STZ-NIR (0.11 ± 0.03 nmoles/mg) compared to CON (0.03 ± 0.01 nmoles/mg) rats. CONCLUSIONS: Hyperglycemia impairs the oxidative balance by increasing reactive oxygen species production and oxidative stress. Increasing evidence supports the hypothesis that oxidative stress contributes to the progression of diabetes and to its complications, which include muscle atrophy. Previous studies in our laboratory have demonstrated the cytoprotective actions of 670 nm light treatment in vitro and in vivo. The present study extends these findings to include the attenuation of oxidative stress in skeletal muscle using a type I model of diabetes.

ATF‐1 is a hypoxia responsive transcriptional activator of UCP3

Uncoupling protein 3 (UCP3) confers resilience against oxidative stress in skeletal muscle. We find a marked upregulation of UCP3 expression in response to hypoxia in mice and in skeletal myotubes. Furthermore, in primary myocytes deficient in UCP3, basal and hypoxia-induced ROS levels are elevated. To investigate the regulation mechanism, a transcription factor transfection array of 704 full-length cDNAs in conjunction with a murine UCP3 promoter-luciferase construct was carried out and ATF-1 was identified as a transcriptional activator of UCP3. Site-directed mutagenesis and ChIP assays identify a 10 bp region necessary for ATF-1 induction of UCP3 promoter activity. Hypoxia promotes the phosphorylation of ATF-1 and its depletion by shRNA prevents hypoxia mediated upregulation of UCP3. Pharmacologic inhibition of p38MAP kinase prevents both hypoxia-mediated ATF-1 phosphorylation and UCP3 upregulation. Interestingly, neither PKA signaling nor HIF-1a activation by cobalt chloride modulates skeletal muscle UCP3 protein levels. In conclusion these data identify that ATF-1, via p38MAPK upregulates UCP3 expression in response to hypoxia and identifies a novel regulatory program orchestrating skeletal muscle anti-oxidant defense. Funded by Intramural Research of NHLBI/NIH.

Calorie restriction attenuates age‐related iron accumulation and oxidative stress in skeletal muscle and improves indices of sarcopenia

Calorie restriction attenuates age‐related iron accumulation and oxidative stress in skeletal muscle and improves indices of sarcopenia

PGC‐1α plays a protective role against oxidative stress in skeletal muscle

PGC‐1α is a transcription coactivator that regulates various biological processes such as mitochondria biogenesis, fatty acid oxidation, and oxidative fiber determination. It has also been shown to regulate genes of the reactive oxygen species (ROS) detoxifying systems. We hypothesize that PGC‐1α plays a protective role against oxidative stress in the highly oxidative tissue, skeletal muscle. To test this hypothesis, we will use a PGC‐1α transgenic mouse (PGC‐1α Tg+/0) that has ubiquitously elevated PGC‐1α in all tissues. We will study primary myoblasts and skeletal muscle tissue to examine the effect of increased PGC‐1α level on the ability to protect against oxidative stress in vitro and in vivo. PGC‐1α protein is overexpressed by 40% in skeletal muscle from the PGC‐1α Tg+/0mice and levels of downstream targets mtTFA, COX II, COX IVa are elevated as measured by real‐time PCR. Muscle mitochondrial ATP generation is unchanged, yet mitochondrial hydrogen peroxide (H2O2) production is significantly reduced by 50%. In a sciatic nerve cut denervation model known to increase muscle mitochondrial ROS generation, PGC‐1α transgenic mice appear to have attenuated release of H2O2. In addition, primary myoblasts exhibited increased resistance to hydrogen peroxide toxicity. In conclusion our data support a significant role for PGC‐1α in protection against oxidative stress in skeletal muscle.

Oxidative stress induced mitochondrial dysfunction leads to age related loss of muscle mass via myonuclear apoptosis and proteolysis

Aging is accompanied by the loss of skeletal muscle mass and function (sarcopenia). Mice lacking the antioxidant enzyme CuZnSOD (Sod1−/−) exhibit high oxidative stress in skeletal muscle and an accelerated sarcopenia. Mitochondria isolated from Sod1−/− muscle generates significantly elevated levels of H2O2 and show a decline in mitochondrial function. We hypothesized that the accelerated sarcopenia in Sod1−/−mice, is due to increased mitochondrial oxidative damage which results in apoptotic deletion of myonuclei and proteolysis. Sod1−/− muscle mitochondria show increased levels of cytochrome c and apoptosis inducing factor (AIF) release. These data are supported by an increase in downstream events; caspase‐9, caspase‐3 activity, DNA fragmentation, and cell‐free apoptosis. However, the myonuclear domain (myofiber volume/myonuclei) is not affected by myonuclear apoptosis. Therefore, it is likely that muscle cells respond to apoptosis by reducing its size via proteolysis. Indeed, cysteine protease, calpain and the 26S proteasome activity is increased by approximately 15~20% along with increased overall ubiquitinylation in Sod1−/− skeletal muscle. Overall, our data support the hypothesis that oxidative stress induced mitochondrial dysfunction leads to myonuclear apoptosis and proteolysis. This could be a possible underlying mechanism of age related muscle loss and function.

670 nm LED Treatment Affects Hyperglycemia‐Induced Oxidative Stress in Skeletal Muscle in Diabetic Rats

Oxidative stress is important in the pathogenesis of diabetes‐induced muscle atrophy. Low energy photon irradiation with 670 nm light has been shown to attenuate oxidative stress following ischemia‐reperfusion injury in the heart. PURPOSE: To determine if 670 nm LED treatment (NIR) would attenuate oxidative damage in a model of type I diabetes, the streptozotocin (STZ)‐treated rat. METHODS: Wistar rats were divided into three treatment groups: Control (CON), STZ‐treated (STZ) and 670 nm LED treated STZ (NIR‐STZ). Diabetes was induced by STZ (50 mg/kg, ip). NIR‐STZ animals were treated once per day for 5 min for 17 days with 670 nm LED arrays (6 joules/cm2; QDI, Barneveld, WI). Animals were euthanized on day 18 and the rectus femoris (RF) muscle was dissected and flash frozen for biochemical analysis of lipid peroxidation. RESULTS: Lipid peroxidation in the RF was slightly increased in the STZ and NIR‐STZ groups relative to control. Total antioxidant capacity in the RF was increased in STZ and NIR‐STZ rats when compared to that of the CON. CONCLUSIONS: Hyperglycemia increased the production of reactive oxygen species. In the acute stage of diabetes, antioxidant proteins are upregulated in response to oxidative stress and protect against lipid peroxidation. Diabetic animals treated with 670 nm light exhibited an additional increase in antioxidant capacity. Funded by: Biomedical Technology Alliance Award and UWM RGI.

Exercise training improves the exercise pressor reflex dysfunction via ameliorating the skeletal muscle oxidative stress in chronic heart failure

In chronic heart failure (CHF), overactive skeletal muscle exercise pressor reflex (EPR) contributes to the exaggerated cardiovascular activity. It has been shown that exercise training (EX) improves the cardiovascular reflexes via ameliorating oxidative stress in CHF. In the present study, we tested the hypothesis that 6–8 weeks EX improved EPR in CHF rats via the mechanism of superoxide. EPR was elicited by electrical stimulation of L4/L5 ventral roots in the decerebrate rats. Superoxide fluorescence in the triceps surae muscle was enhanced in CHF rats compared with sham rats, which was reduced in EX+CHF rats. As shown in table, the EPR response in CHF rats was higher than in sham rats, and the intra‐arterial infusion of a superoxide dismutase (SOD) mimetic (tempol) normalized the EPR in CHF rats. EX improved the augmented EPR in CHF rats, which was abolished by the intra‐arterial infusion of a SOD inhibitor (DETC). The data suggest that EX improves the EPR dysfunction in CHF probably by ameliorating the muscle oxidative stress.

The Effect of Muscle-Damaging Exercise on Blood and Skeletal Muscle Oxidative Stress

The aim of this article is to present the effects of acute muscle-damaging exercise on oxidative stress/damage of animal and human tissues using a quantitative approach and focusing on the time-course of exercise effects. The reviewed studies employed eccentric contractions on a dynamometer or downhill running. The statistical power of each study to detect a 20% or 40% post-exercise change compared with pre-exercise value in each oxidative stress/damage biomarker was calculated. Muscle-damaging exercise can increase free radical levels and augment oxidation of lipids, proteins, glutathione and possibly DNA in the blood. In contrast, the effect of muscle-damaging exercise on concentration of antioxidants in the blood, except for glutathione, was little. Muscle-damaging exercise induces oxidative stress/damage in skeletal muscle, even though this is not fully supported by the original statistical analysis of some studies. In contrast, muscle-damaging exercise does not appear to affect--at least to similar extent as the oxidative stress/damage markers--the levels of antioxidants in skeletal muscle. Based on the rather limited data available, the oxidative stress response of skeletal muscle to exercise was generally independent of muscle fibre type. Most of the changes in oxidative stress/damage appeared and were sustained for days after muscle-damaging exercise. The major part of the delayed oxidative stress/damage production that follows muscle-damaging exercise probably comes from phagocytic cells that are activated and recruited to the site of the initial damage. A point that emerged and potentially explains much of the lack of consensus among studies is the low statistical power of many of them. In summary, muscle-damaging exercise can increase oxidative stress/damage in blood and skeletal muscle of rats and humans that may persist for and/or appear several days after exercise.

Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats

BackgroundHuman immunodeficiency virus type 1 (HIV-1) infection and the consequent acquired immunodeficiency syndrome (AIDS) has protean manifestations, including muscle wasting and cardiomyopathy, which contribute to its high morbidity. The pathogenesis of these myopathies remains partially understood, and may include nutritional deficiencies, biochemical abnormalities, inflammation, and other mechanisms due to viral infection and replication. Growing evidence has suggested that HIV-1-related proteins expressed by the host in response to viral infection, including Tat and gp120, may also be involved in the pathophysiology of AIDS, particularly in cells or tissues that are not directly infected with HIV-1. To explore the potentially independent effects of HIV-1-related proteins on heart and skeletal muscles, we used a transgenic rat model that expresses several HIV-1-related proteins (e.g., Tat, gp120, and Nef). Outcome measures included basic heart and skeletal muscle morphology, glutathione metabolism and oxidative stress, and gene expressions of atrogin-1, muscle ring finger protein-1 (MuRF-1) and Transforming Growth Factor-β1 (TGFβ1), three factors associated with muscle catabolism.ResultsConsistent with HIV-1 associated myopathies in humans, HIV-1 transgenic rats had increased relative heart masses, decreased relative masses of soleus, plantaris and gastrocnemius muscles, and decreased total and myosin heavy chain type-specific plantaris muscle fiber areas. In both tissues, the levels of cystine (Cyss), the oxidized form of the anti-oxidant cysteine (Cys), and Cyss:Cys ratios were significantly elevated, and cardiac tissue from HIV-1 transgenic rats had altered glutathione metabolism, all reflective of significant oxidative stress. In HIV-1 transgenic rat hearts, MuRF-1 gene expression was increased. Further, HIV-1-related protein expression also increased atrogin-1 (~14- and ~3-fold) and TGFβ1 (~5-fold and ~3-fold) in heart and plantaris muscle tissues, respectively.ConclusionWe provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication. Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies. If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.

Prior exercise and antioxidant supplementation: effect on oxidative stress and muscle injury

BackgroundBoth acute bouts of prior exercise (preconditioning) and antioxidant nutrients have been used in an attempt to attenuate muscle injury or oxidative stress in response to resistance exercise. However, most studies have focused on untrained participants rather than on athletes. The purpose of this work was to determine the independent and combined effects of antioxidant supplementation (vitamin C + mixed tocopherols/tocotrienols) and prior eccentric exercise in attenuating markers of skeletal muscle injury and oxidative stress in resistance trained men.MethodsThirty-six men were randomly assigned to: no prior exercise + placebo; no prior exercise + antioxidant; prior exercise + placebo; prior exercise + antioxidant. Markers of muscle/cell injury (muscle performance, muscle soreness, C-reactive protein, and creatine kinase activity), as well as oxidative stress (blood protein carbonyls and peroxides), were measured before and through 48 hours of exercise recovery.ResultsNo group by time interactions were noted for any variable (P > 0.05). Time main effects were noted for creatine kinase activity, muscle soreness, maximal isometric force and peak velocity (P < 0.0001). Protein carbonyls and peroxides were relatively unaffected by exercise.ConclusionThere appears to be no independent or combined effect of a prior bout of eccentric exercise or antioxidant supplementation as used here on markers of muscle injury in resistance trained men. Moreover, eccentric exercise as used in the present study results in minimal blood oxidative stress in resistance trained men. Hence, antioxidant supplementation for the purpose of minimizing blood oxidative stress in relation to eccentric exercise appears unnecessary in this population.

Aging Augments Oxidative Stress In Skeletal Muscle During Suspension-induced Unloading

Oxidative stress increases during hindlimb suspension in muscle from young adult animals. However, it is not known if oxidative stress is also increased in a similar fashion during unloading in aged skeletal muscle. Therefore, the PURPOSE of this study was to test the hypothesis that aging augments oxidative stress during muscle unloading-induced atrophy. METHODS: By using the techniques of RT-PCR, western immunobloting and other biochemical assays, the present study examined the markers of oxidative stress and antioxidant enzymes gene and protein expressions in gastrocnemius muscles of young adult and aged Fischer344xBrown Norway rats after 14 days of hindlimb suspension. RESULTS: Sarcopenia was observed when comparing both muscle wet weights and muscle weight normalized to body weight between young adult and aged animals. As expected, muscle mass decreased after suspension in both young adult and aged animals. The contents of MDA/4-HAE and nitrotyrosine and the catalase activity were greater in unloaded relative to control muscles in young adult and aged animals. H2O2 content was elevated while MnSOD protein content was reduced in suspended muscles when compared to control muscles exclusively in the aged animals. Changes in oxidative stress markers MDA/4-HAE, H2O2 and MnSOD protein contents to hindlimb unloading occurred in an age-dependent manner. The age-related decrease in muscle mass was accompanied by greater catalase activity and contents of H2O2, 8-OHdG and nitrotyrosine but lower abundances of MnSOD mRNA and protein and catalase mRNA, relative to muscles from young adult animals. CONCLUSIONS: These findings are consistent with the hypotheses that oxidative stress has a role in mediating disuse-induced and sarcopenia associated muscle losses. Our data suggest that aging may predispose skeletal muscle to increased levels of oxidative stress both at rest and during unloading.