Resveratrol and muscle recovery -
Digital records of the bands were captured using a Kodak camera and quantified using one-dimensional analysis software Eastman Kodak as optical density × band area, expressed in arbitrary units relative to appropriate loading controls.
Frozen tissue μm thick cross sections were obtained from the plantaris muscles and mounted on charged microscope slides Fisher Scientific; Pittsburgh, PA. Fluorescent labeling of terminal dUTP nick-end labeling TUNEL with lamina allowed the detection of apoptotic nuclei in the muscle sections.
This was accomplished using a slight modification to the method previously reported for our lab [ 29 ]. The tissues were incubated overnight at 4°C in a rat anti-lamina monoclonal antibody Millipore. Sections were incubated the following day with donkey anti-rat rhodamine conjugated secondary antibody Jackson ImmunoResearch , along with the TUNEL reaction mixture ; Roche Diagnostics; Indianapolis, IN in a humidified chamber at 37°C for 1 hour in the dark.
The exclusion of the TdT enzyme in the TUNEL reaction mixture on one of the tissue sections on each slide was included as a negative control. The sections were mounted with DAPI Vectashield in order to visualize nuclei and viewed under a Zeiss LSM Meta confocal microscope Carl Zeiss Microimaging Inc.
The number of TUNEL and DAPI-positive nuclei that were immediately adjacent to, or beneath the basal lamina were counted. The data are expressed as an apoptotic index, calculated as the percentage of TUNEL-positive nuclei out of the total myonuclei i.
The apoptotic index was determined from four non-overlapping regions of each tissue cross section visualized with a 20X objective. Frozen tissue cross sections measuring μm thick from the plantaris muscle were mounted on charged microscope slides Fisher Scientific; Pittsburgh, PA.
Briefly, tissue sections were air dried, washed in PBS, fixed in methanol: acetone at °C for 5 minutes, and permeabilized with 0. Sections were then denatured, blocked with serum and incubated overnight in a biotinylated mouse anti-BrdU primary antibody HCS30, EMD Biosciences, Inc.
On the following day, the sections were incubated with a secondary antibody of Fluorescein Avidin DCS A; Vector Laboratories, Inc. They were then incubated overnight in a rat anti-lamina monoclonal Millipore primary antibody. The tissue sections were incubated the following day with a donkey anti-rat rhodamine conjugated Jackson ImmunoResearch secondary antibody in a humidified chamber at 37°C for 1 hour in the dark.
Finally, the sections were mounted with 4',6-diamidinophenylindole DAPI -containing mounting medium Vectashield in order to visualize nuclei. Immunofluorescence was visualized with a Zeiss LSM Meta confocal microscope Carl Zeiss.
Images were taken from four non-overlapping regions of each tissue section with a 20X objective. All results are reported as means ± SD. Differences in means between groups were determined by multiple analysis of variance MANOVA Hotelling's T-Square test. Bonferroni post hoc analyses were subsequently performed between significant means.
We measured the bodyweight of all animals at the beginning of the one-week pretreatment period Start , immediately prior to suspension Day 0 , following hindlimb suspension, and following the recovery period. There were no differences in bodyweight between any of the groups at the beginning of the experimental protocol.
Furthermore, no significant changes in bodyweight were observed in the cage control animals at any of the time points. A significant loss of bodyweight occurred in all of the suspended animals as compared to the first day Start of the experiment, with decreases of These significant losses continued into the recovery period as well, with vehicle and resveratrol treated animals losing an additional 3.
However, resveratrol was unable to attenuate any of these bodyweight reductions, as there were no significant differences observed between the vehicle and resveratrol treated animals at any of the individual time points of the study Figure 1A. Plantaris muscle wet weights were obtained following HS or R.
cage control. Upon sacrifice, the plantaris muscle wet weights were examined to assess changes in muscle mass following the suspension and recovery periods. However, there were no differences between the vehicle and the resveratrol treated animals.
Plantaris muscles were attached to a force transducer in oxygenated Ringers solution, to determine various muscle contractile properties following hindlimb suspension and recovery. However, resveratrol was unable to attenuate this increase Figure 2A. In the recovery group, the CT of both the vehicle There were no differences observed when comparing the CT of the vehicle and resveratrol treated animals.
Muscle twitch contractile properties including CT and ½ RT were analyzed in the plantaris muscles of both the hindlimb suspension A and recovery B groups. Each data point represents the average of three measures. Next, we examined the ½ RT during a twitch contraction.
In the hindlimb suspension group, the ½ RT was significantly shorter in the vehicle treated Moreover, there were no differences between the resveratrol and cage control groups at this time point.
This same trend also continued into the recovery period Figure 2B. While there were no differences in the ½ RT between the resveratrol Lastly, we plotted the force-frequency curve for the hindlimb suspension and recovery groups.
In the hindlimb suspension animals, a frequency of 20 Hz produced a significant rightward shift in both the vehicle and resveratrol treated groups Figure 3A.
At 50 Hz, there remained a significant rightward shift in the resveratrol animals curve compared to both the cage control and vehicle treated animals. In contrast, there were no differences observed between the vehicle treated and cage control groups. At 75 Hz, both the vehicle and resveratrol treated groups reached their peak relative forces.
A force-frequency curve was plotted for both the hindlimb suspension A and recovery B groups. Each force-frequency measurement was made three times with a minimum of 5 minutes rest between each contraction, and the average of the three trials was recorded for each animal.
In the recovery animals, the force frequency curves from both the vehicle and resveratrol treated groups were significantly shifted to the right of the cage control curve at 10, 20, and 50 Hz Figure 3B. However, the force-frequency curves of the vehicle and the resveratrol groups did not differ.
The force record at 75 Hz in the resveratrol treated animals had a significant rightward shift as compared to the cage controls. The fatigue index was examined in order to determine if resveratrol had improved the muscles fatigue tolerance during a series of contractions.
Both the vehicle However, there were no differences observed between the resveratrol and the vehicle treated animals. In the recovery animals, the vehicle treated animals had a similar fatigue index Plantaris muscle fatigability was expressed as a fatigue index, and calculated as the percent of the initial force average of the first three contractions, divided by the force at the end of the fatigue protocol an average of the force generated in the final three contractions in a series of consecutive contractions.
The plasma level of resveratrol, in resveratrol-treated animals averaged There were no differences between the animals in the hindlimb suspension or control groups.
Metabolites of resveratrol were similarly very high in the resveratrol treated animals Table S1. While there were no traces of resveratrol in the plasma of any of the vehicle treated animals, there was a detectible about of several resveratrol metabolites in the plasma of vehicle treated animals Table S1 suggesting that perhaps the control diet contained small but detectable levels of resveratrol which had been metabolized by the vehicle-treated animals.
The relative activity of Sirt1 in the plantaris muscles of all of the animals was assessed using a fluorometric assay. In the hindlimb suspension animals, there were no significant differences in Sirt1 activity between any of the groups, although there was a trend towards higher levels in the resveratrol treated animals Figure 5.
This trend continued with the recovery groups as well, although the differences between the groups were less than it was in the hindlimb suspension animals.
This was due to a slight elevation in Sirt1 activity in the muscles of both the recovery control and the vehicle treated animals as compared to their respective hindlimb suspension groups. Western blots were conducted for plantaris muscles after hindlimb suspension or following recovery from hindlimb suspension.
The protein content was measured in total plantaris muscle homogenates via immunoblotting. The proteins were electroblotted to nitrocellulose membranes and the signals were developed by chemiluminescence.
The proteins included phosphorylated activated AMPK, total AMPK, PGC1α, and Sirt1. GAPDH was used as an internal loading control.
Con, control; Veh, vehicle-treated; Res, resveratrol treated. The digital images of the western blots were quantified as optical density x band area using ImageJ software and normalized to GAPDH, which was used as the loading control for each lane.
The data include: B , total AMPK; C. phosphorylated AMPK pAMPK ; D. PGC1α; and E. The data are expressed as the protein signal to the GAPDH signal and are reported as mean ± SEM in arbitrary units.
A minimum of three western blots were completed for each protein, and the data were averaged for each animal. Sirt1 enzyme activity was determined fluorometrically in plantaris muscle homogenates. Resveratrol treatment elevated AMPK and pAMPK abundance in the plantaris of resveratrol-fed animals in the recovery group as compared to the vehicle treated or control animals Figure 5.
Sirt1 protein abundance was not improved by resveratrol treatment Figure 5. However, resveratrol, appeared to increase the protein abundance of PGC1α, a downstream target of Sirt1, in the plantaris muscles of animals in the recovery group fed resveratrol, as compared to vehicle treated animals.
We did not determine if mitochondrial biogenesis had been altered by resveratrol treatment in the muscles of these animals, however, this seems unlikely since the fatigue characteristics of the muscles was not improved by resveratrol treatment. The myosin heavy chain expression was identified in the plantaris muscles fibers by immunocytochemistry Figure 6.
This provided both an index of fiber type and also fiber size. Typically, hindlimb suspension results in a shift from type I to type II fibers.
To determine if resveratrol reduced this fiber type shift following hindlimb suspension or recovery, we examined the myosin heavy chain MyHC profile of the plantaris muscles.
Following hindlimb suspension, the relative percentage of type I MyHC fibers was significantly reduced in both of the groups subjected to suspension. However, there were no differences between MyHC composition in the vehicle and the resveratrol treated animals, although the mean percentage was slightly higher in the resveratrol group Figure 7A.
The resveratrol treated animals in the hindlimb suspension group, had a greater percentage of type IIA MyHC fibers, than either the vehicle treated suspended animals, or cage control animals.
Suspension significantly increased the percentage of type IIB fibers, although resveratrol had no effect on changes in this fiber type compared to the vehicle treatment. In contrast, the percentage of type IIX MyHC fibers was significantly reduced after suspension in the resveratrol treated animals from that of the control muscles.
However, there were no significant differences between the two suspended groups. Frozen tissue cross sections were incubated overnight at 4°C with antibodies directed against the basal lamina red and myosin heavy chain I, IIA, or IIB green.
The sections were counterstained with DAPI blue to identify the nuclei. Digital images were taken with a confocal microscope. This figure provides a representative example of a section stained for type I myosin heavy chain that was used to measure fiber type composition and CSA analyses for this fiber type in both the hindlimb suspension and recovery groups.
Green fibers are positive for type I myosin heavy chains. Scale bars represent 50 µm. Immunocytochemical stained plantaris muscle fibers for myosin heavy chains, from control, vehicle-treated and resveratrol-treated rats were analyzed for their myosin heavy chain fiber composition in both the hindlimb suspension A and recovery B groups.
The percentage of type I fibers remained significantly less in the animals in the recovery group that had previously been suspended.
However, there was an increase in the percentage of type I fibers in the vehicle treated animals to where the resveratrol treated animals no longer had a greater proportion of this fiber type Figure 7B. While the percentage of type IIB fibers remained significantly elevated in both the vehicle and the resveratrol treated animals in the recovery group as compared to the control group, there remained no differences between these treatment groups.
There was no difference between the percentage of type IIX MyHC fibers in the recovery group of resveratrol and the vehicle treated animals. Muscle fiber CSA was determined by planimetry in type I, IIA, and IIB MyHC fibers Figure 6. As expected, hindlimb suspension induced significant muscle atrophy in all of the fiber types examined.
There were no differences in mean type I fiber CSA between the vehicle and resveratrol treated animals after hindlimb suspension, although both hindlimb suspension treatment groups had significantly smaller fibers than the cage control animals.
The mean fiber CSA from the resveratrol treated animals in the hindlimb suspension group was not different than the cage control animals, indicating that resveratrol partially preserved muscle fiber area during hindlimb suspension in this particular fiber type.
Type IIB MyHC fibers CSA was significantly smaller in both the vehicle and the resveratrol treated groups as compared with the fiber CSA from cage control animals. However, no significant differences were noted between type IIB fiber CSA in the vehicle and resveratrol treated groups following hindlimb suspension.
Mean fiber cross sectional area CSA measurements were obtained from a minimum of fibers in each muscle for plantaris muscle fibers that expressed type I, IIA, or IIB myosin heavy chains in hindlimb suspension A and recovery B groups.
Four images from non-overlapping regions of each tissue cross-section stained for individual MyHC fibers were used for muscle fiber CSA measures.
All images were taken with a Zeiss LSM Meta confocal microscope at a magnification of 20X. Mean fiber CSA of respective fiber types was determined by planimetry.
Animals in the recovery group had a similar fiber type pattern as was found in muscles from the hindlimb suspension animals Figure 8B.
This suggests that there was no substantial return to control levels in fiber type distribution during the recovery period. Specifically, type I fibers CSA remained significantly smaller in both the vehicle and resveratrol treated animals as compared to the cage controls.
Mean type IIA fiber CSA was significantly reduced in the vehicle treated animals as compared to the cage control animals. Moreover, although the mean type IIB fiber CSA remained significantly reduced in the vehicle treated animals, the mean CSA of the resveratrol treated animals somewhat recovered and so that fiber CSA was no longer statistically smaller than the control fibers.
A BrdU pellet was implanted subcutaneously at point that hindlimb suspension was removed, in each of the recovery animals to identify satellite cells that had proliferated during the regenerative period following hindlimb suspension.
BrdU-positive nuclei were expressed per myonuclei. BrdU incorporation was very low in muscles of the cage control animals 0. Presumably, there was minimal stimulus to activate any available satellite cells from quiescence under these homeostatic conditions Figure 9.
It was not surprising that there was a significant increase in BrdU incorporation in both the vehicle 7. While there was a trend for slightly more BrdU positive nuclei in resveratrol treated muscles, this was not significantly different from the vehicle group.
In order to analyze satellite cell proliferation during the reloading period, a time-released BrdU pellet was inserted into the recovery animals at the point that they were released from suspension. BrdU is a thymidine analogue and it was incorporated into muscle nuclei satellite cells that divided.
A representative section from the plantaris of a resveratrol-treated animal that was reloaded for 14 days following 14 days of hindlimb suspension. The tissue was stained with DAPI to identify all of the nuclei, an anti-BrdU antibody to identify nuclei that had proliferated, and an anti-laminin antibody to identify the basal lamina.
The overlay shows the three fluorescent images superimposed. The expanded insert shows examples of BrdU positive nuclei that are co-localized to the DAPI stained myonuclei over the basal lamina white arrows.
Other examples of non-specific green staining not on nuclei are evident, but they were not included in the quantification of BrdU positive nuclei.
BrdU incorporation in muscle nuclei i. We have previously characterized apoptotic protein changes during hindlimb suspension and reloading [ 13 , 30 ].
In the current study, western blots were used to determine the relative content of anti-apoptotic Bcl-xL and Bcl-2 and pro-apoptotic Bax, cleaved caspase 3 and cleaved caspase 9 proteins, as representative of changes in the apoptotic signaling pathway. Protein levels of the respective proteins were normalized to GAPDH protein levels and were expressed in arbitrary units.
Although resveratrol did not reduce the hindlimb suspension-induced elevation in Bax, in the recovery group, the pro-apoptotic Bax protein abundance was lower in resveratrol than vehicle treated plantaris muscles Figure In a similar pattern, pro-apoptotic proteins cleaved caspase 3 and cleaved caspase 9 were elevated by hindlimb suspension, but the increases in cleaved caspase 9, a mitochondrial-associated pro-apoptotic protein was suppressed by resveratrol.
Resveratrol suppressed both cleaved caspase 3 and cleaved caspase 9 in the plantaris muscles of the recovery group as compared to the vehicle treated group Figure Bcl-2 was elevated in a similar fashion in vehicle treated and resveratrol treated plantaris muscles during hindlimb suspension Figure During recovery, the Bcl-2 protein abundance returned to control levels in the vehicle-treated plantaris muscle, but it remained elevated in plantaris muscles that were treated with resveratrol.
The protein abundance of the anti-apoptotic Bcl-xL was significantly increased in the resveratrol group following hindlimb suspension, while no changes were observed in the vehicle 0.
During recovery, the abundance of Bcl-xL was elevated in both the vehicle 0. Representative western blots of apoptotic proteins. Bax, Bcl-xL, Bcl-2, cleaved caspase 3 CC-3 , cleaved caspase 9 CC-9 and GAPDH. The digital images were quantified as optical density x band area using ImageJ software and normalized to GAPDH, which was used as the loading control for each lane.
These data include: Bax B Bcl-2 C , Bcl-xL D , cleaved caspase 3 E , and cleaved caspase 9 F. To complement the western blot analysis, we used a TUNEL assay to confirm the relative amount of myonuclei undergoing apoptosis immediately following hindlimb suspension Figure 11A and recovery Figure 11B.
Consistent with our previous observations [ 13 , 30 ], there was a significant increase in apoptosis following hindlimb suspension Figure 11C. In the recovery group, the TUNEL index remained significantly elevated in both the vehicle 1.
DNA fragmentation was assessed with TUNEL staining green as an indication of nuclei committed to apoptosis in the plantaris muscles from animals. The basal lamina of the muscle fibers was incubated in an anti-lamina antibody red to identify nuclei adjacent to or inside the basal lamina of the fibers.
Representative tissue cross sections are shown for animals in the hindlimb suspension A and recovery B groups. Now let me tell you my view on this topic: I think that when one performs exercise, a small amount of radicals occur, and this has a hormetic like a vaccination effect.
A few radicals enormously activate the antioxidant defenses, and these are good for you. These radicals also activate the mitochondriogenic pathway. Thus, it is not advisable to take antioxidants when you are training because it hampers the beneficial effects of training. When do I recommend antioxidants?
Before a competition. In competitions, the effort is likely to be very heavy and sometimes taken to the very limit of the individual athlete. In this case, the free radicals produced in exercise may overwhelm the defenses and then cause damage.
Therefore, I would recommend taking relatively light doses of antioxidant vitamins like 1 g of vitamin C and IU of vitamin E only in cases when people are competing, but not when they are training.
On the other hand, work by Bruce Ames in Berkeley has shown that the vast majority of the population is deficient in one micronutrient or another, and we do not know which ones. For instance, you may be deficient in one vitamin and I may be deficient in one mineral.
The more variety the better. Because the dose is relatively small, no toxic effects are likely to occur. However, since we are administering many different micronutrients, we are likely to cover the deficiencies in these micronutrients.
The findings of Gliemann et al extend those of others such as Ristow et al 3 that one good thing ingestion of resveratrol at appropriate doses may blunt the positive effects of another i.
While more research needs to be done on this important area, the original and seminal observations of Ristow and colleagues that some of the benefits of exercise are mediated via reactive oxygen and that these benefits can be blocked by the ingestion of high levels of antioxidants was supported.
The fact that low levels of ROS play an important role in promoting health represents a fundamental change in biological understanding, whereby in the past it was assumed that even low dose of ROS were universality harmful. Now we know that they are essential.
The implications of this new understanding are extremely important, especially in the areas of drug development, environmental regulation and in activities eg, diet, exercise associated with lifestyle.
Healthcare Perspectives. Muscle strength was evaluated by quantitative muscle testing QMT 16 , 17 , QMT was performed using a hand-held dynamometer μTas F-1; ANIMA Co.
Pinch, grip, scapula elevation, shoulder abduction, elbow flexion, elbow extension, hip flexion, knee extension, and ankle dorsiflexion were measured. Pulmonary function tests and blood were examined at Sapporo Medical University Hospital, and resveratrol concentration was measured by liquid chromatography—tandem mass spectrometry at Toray Research Center Tokyo, Japan.
Adverse events were classified, and their degree of severity was determined according to the Common Terminology Criteria for Adverse Events CTCAE v. As the primary endpoint, the MFM score, QMT score, and CK value were evaluated as continuous variables.
All data and average values at each visit were plotted. For the QMT score, participants in whom the baseline value of each item could not be measured were excluded.
Statistical analyses were performed using SPSS v. Study approval The protocol was approved by the IRB of Sapporo Medical University Hospital on May 12, The protocol was then slightly modified twice and approved by the IRB on Sep.
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Arch Neurol. Download references. This study was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology for Translational Research Seed A ; the Japanese Society for the Promotion of Science JSPS KAKENHI Grant Numbers, 15K and 18K ; the Setsuro Fujii Memorial, the Osaka Foundation for Promotion of Fundamental Medical Research; and the Hiroshige Kondo Foundation.
We thank Shun Shimohama, Tomihiro Imai, Shin Hisahara Department of Neurology, Sapporo Medical University School of Medicine and Tomoyuki Dobata Toseikai Healthcare Corporation, Life-Long Care Clinic for Disabled People for the referral of patients.
Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, , Japan. Faculty of Health Science, Hokkaido Chitose College of Rehabilitation, Chitose, , Japan. Department of Physical Therapy, Sapporo Medical University School of Health Sciences, Sapporo, , Japan.
Biostatistics Division, Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, , Japan. Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, , Japan.
Department of Biostatistics, Sapporo Medical University School of Medicine, Sapporo, , Japan. Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, , Japan. You can also search for this author in PubMed Google Scholar. designed the study.
Brian T. BennettLunch timing Virginia University Junaith S. MohamedRecovrey Resveratrol and muscle recovery University Eye health formulas Resveratroll. Alway Resverahrol, West Virginia University. Aging is associated with poor skeletal muscle regenerative ability following extended periods of hospitalization and other forms of muscular disuse. As muscle disuse and reloading after disuse increases oxidative stress, we hypothesized that resveratrol supplementation would improve muscle regeneration after disuse.
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