A further aim was to examine whether the training effects on muscle quantity and stiffness would differ depending on the dose of QGs. A randomized, double-blind, placebo-controlled, parallel-group, comparative study was designed to evaluate the effects of two different doses of QG supplementation with resistance training on muscle quantity and stiffness.

Community-dwelling Japanese people living in Osaka were recruited, and participants were screened. Fifty-four participants were randomly allocated to the placebo with exercise placebo , mg of QGs with exercise low-QG , and mg of QGs with exercise high-QG groups.

Randomization was performed based on dynamic allocation to maintain balance among the groups in age, sex, and leg muscle mass using a spreadsheet program with the RAND function Microsoft Excel , Microsoft Corporation, Redmond, WA, United States.

The randomization codes for both participants and groups were held in sealed opaque envelopes by two different individuals who were not engaged in the present study.

A research nurse kept the envelopes closed until all data were collected and analyzed. The interventions for the 24 weeks of the present study were performed between August and March Magnetic resonance imaging MRI , dual-energy X-ray absorptiometry DXA , and ultrasound shear wave elastography SWE measurements were performed at baseline, at 12 weeks, and at 24 weeks during the intervention.

Blood and urine were sampled following overnight fasting for safety assessment in the screening period, at baseline, at 12 weeks, and at 24 weeks. All participants recorded changes in physical condition and habituation during the intervention period because they were instructed not to change their lifestyles, especially exercise habits, and their compliance with the exercise intervention and capsule intake were checked regularly.

The Ethics Committee of The Fukuda Clinic and Ritsumeikan University approved the study protocol in compliance with the Declaration of Helsinki. All participants provided their written, informed consent prior to their inclusion in the present study.

The present study was registered in the University Hospital Medical Information Network UMIN Clinical Trial Registry UMIN The participants were community-dwelling Japanese men and women, aged 50—74 years, not engaging in exercise regularly, that is not more than twice a week and more than 30 min per times, in the past year before starting the screening.

Exclusion criteria were: the presence of disease affecting the locomotor organs; the presence of cardiovascular disease limiting exercise intervention; a history of serious disorders and clinically significant systemic diseases; having problems doing the exercise intervention; planning weight loss; having previous experience with high-intensity exercise, such as bodybuilder; an irregular lifestyle; a heavy drinker or smoker; consumption of drugs or supplements that affect efficacy evaluation; consumption of drugs consecutively during interventions; not capable of undergoing MRI measurements, such as having magnetic material, a tattoo on the body, or claustrophobia; not capable of swallowing capsules; pregnant women; nursing mothers or women of child-bearing potential; and the presence of any medical condition judged by the medical investigator to be incompatible with participation in the present study.

The primary outcome in the present study was the change in thigh muscle CSA on MRI over 24 weeks. Secondary outcomes were changes in vastus lateralis VL muscle CSA, whole-body lean mass by DXA, and shear wave velocity SWV, an index of tissue stiffness in three different positions by SWE.

Safety was assessed based on the incidence of side effects and adverse events, such as feeling cold, lassitude, or muscular pain, among the groups during the week intervention.

To evaluate muscle CSAs, a 3. The images of the right midthigh at the center of the end-to-end images from the mm-thick slices were analyzed to measure thigh and VL muscle CSAs by SliceOmatic Ver 4. Dual-energy X-ray absorptiometry Lunar iDXA; GE Healthcare United Kingdom Limited, Buckinghamshire, United Kingdom was used for whole-body composition assessment.

Lean mass was obtained from leg, arm, and whole-body regions. All measurements were performed by a medical technologist of Ritsumeikan University.

Shear wave velocity of the right VL was measured by an ultrasound SWE apparatus Aixplorer version 12, Supersonic Imagine, Aix-en-Provence, France with a linear array probe SL , as previously reported 7.

The SWE measurements were performed in this order. The participants were instructed to relax completely throughout the measurements. In each position, three measurements were performed i.

The SWE data were analyzed using the software included with the ultrasound apparatus to calculate SWV over the region of interest, which was as large as possible, in VL without aponeurosis or subcutaneous adipose tissue.

It was confirmed that no pixel in the region of interest reached the saturation limit of SWV For each position, the average of three measurements was used for further analyses. All measurements and analyses of the SWE data were performed by an examiner with more than 5 years of experience.

Participants performed resistance exercise programs 3 days per week every Monday, Wednesday, and Friday for 24 weeks, as previously reported Briefly, a well-trained instructor conducted the training program, which constituted a 5-min warm-up, min resistance training using machines including leg extension, leg curl, leg press, and chest press, and 5-min cool-down.

For evaluating 1-RM, the indirect method of the 1-RM test was used, as previously reported Attendance and numbers of sets completed were checked by instructors to calculate the attendance rates.

Experimental supplements contained mg or mg of QGs. QGs were enzymatically manufactured at San-Ei Gen F. Osaka, Japan from isoquercitrin prepared from quercetin O -rutinoside. Participants took six capsules including 0 mg of QGs placebo group , mg of QGs low-QG group , or mg of QGs high-QG group with the same color.

The weights and volumes of all capsules were adjusted to be equal using dextrin, silicon oxide, and calcium stearate. Compliance with capsule intake in each participant was checked by the study diary.

Per-protocol set PPS analysis was used for efficacy assessment according to the statistical analysis plan. Baseline characteristics were compared among the groups by one-way ANOVA for quantitative variables and the chi-squared test for categorical variables.

Differences between groups over time were analyzed by two-way repeated-ANOVA. The full analysis set was used for safety assessment. Statistical analyses were carried out using IBM SPSS Statistics for Windows, Version Of the 54 participants allocated to the three groups, 3 withdrew consent prior to the intervention or dropped out because of the exclusion criteria.

Another 3 participants were excluded from the analysis because they fulfilled the exclusion criteria. Mean attendance rates during the week resistance exercise program were Mean compliance rates for capsule intake during the week intervention were There were no significant differences in baseline characteristics including age, sex, height, weight, and SMI among the groups Table 1.

Figure 1. Flowchart of this study. Of the participants recruited, 54 were randomly allocated to the placebo, low-QG, and high-QG groups. QG, quercetin glycoside. The combined effects of QG supplementation and resistance training during the week intervention on muscle quantity and stiffness were evaluated using MRI, DXA, and SWE measurements Table 2.

There were no significant differences among the groups in the parameters at baseline. During the week intervention period, a significant group × time interaction was not observed in thigh muscle CSA set as the primary outcome, as well as the VL muscle CSA and lean body mass measured by MRI and DXA.

VL SWV in the knee fully flexed position at 24 weeks was significantly decreased compared with baseline —0. The changes in SWV in the knee fully flexed position over 24 weeks were significantly larger in both the low and high-QG groups than in the placebo group low-QG vs. No correlation was also observed between VL SWV and 1-RM muscular strength Supplementary Figure 1.

Table 2. Effects of the intervention on muscle quantity and stiffness in the PPS analysis. Figure 2. Relationships between muscle quantity and stiffness during the week intervention in the PPS analysis. VL, vastus lateralis; CSA, cross-sectional area; and SWV, shear wave velocity.

No side effects due to QG supplementation were observed. There were no severe adverse events and no significant difference in the incidence of adverse events among the placebo In the present study, the week intervention effects of QG supplementation combined with low-intensity resistance training on muscle quantity and stiffness as an index of fibrosis were investigated in middle-aged and elderly people.

For muscle quantity, there were no significant differences in thigh CSA on MRI between QG supplementation with exercise and placebo with exercise, as well as each lean body mass on DXA.

For muscle stiffness, both and mg QG supplementation with exercise significantly decreased SWV of VL in a stretched position i. This is the first report to show that the combination of nutrition and exercise could improve age-related changes in passive muscle stiffness.

Extracellular matrix components are responsible for muscle stiffness 3 , Thus, it is reasonable to use muscle stiffness as an index of ECM components. Previously, we identified an increase of VL muscle stiffness in full knee flexion from In animal studies, the excessive ECM accumulation in older muscles was reduced by resistance training with change of the gene expression related to ECM turnover 22 , Moreover, the acute stimulus of resistance exercise also decreased the gene expression associated with skeletal muscle ECM remodeling in elderly men However, no longitudinal studies evaluating the effects of exercise on muscle fibrosis caused by aging have been available.

The present study is the first to demonstrate the effects of long-term resistance training on ECM accumulation in middle-aged and elderly people Table 2 , albeit indirectly through muscle stiffness assessment using ultrasound SWE.

Furthermore, QG supplementation with both and mg combined with exercise improved muscle stiffness more than exercise alone Table 2. To support these data, administration of quercetin, an active form of QGs in target tissues, decreased muscle fibrosis by suppressing inflammatory cytokines in mdx mice In addition, no significant correlation was observed between muscle stiffness in the stretched position and muscle CSA in VL, as well as their changes during the week intervention Figure 2 , indicating that the intervention effects on muscle stiffness were independent of those on muscle quantity.

These findings suggest that QG supplementation exerts additive effects on the improvement of passive muscle stiffness with resistance training. Moreover, the effects of various interventions and age-associated differences in muscle stiffness were observed only in stretched positions, but not in shortened positions in the previous studies 7 , 25 , This was consistent with the results of the present study.

Muscle stiffness in stretched positions can reflect the accumulation of ECM components referred to as muscle fibrosis 7. Thus, the present findings indicate that a combination of exercise and QG supplementation improves age-associated muscle fibrosis. The present results showed no correlations between muscle stiffness and 1-RM muscular strength Supplementary Figure 1 , suggesting that muscle stiffness would relate to muscle function other than muscular strength.

Based on the facts that increased muscle stiffness impairs joint flexibility 4 , 27 and that a decline in joint flexibility impairs balance and functional ability 28 , decreasing the quality of life for elderly people, the reduction in muscle stiffness by exercise and QG supplementation observed in the present study would contribute to increased joint flexibility, and then improve the quality of life in elderly people, although further studies are needed to clarify this hypothesis.

In terms of the effects of QG supplementation on muscle quantity, PPS analysis showed no significant group × time interaction in muscle CSAs and lean mass Table 2 , suggesting that combined effects of QG supplementation and exercise on muscle quantity were not observed in the present study.

Previous studies in animals indicated that quercetin, an active form of QGs, prevented muscle atrophy by suppressing ubiquitin proteasome system-induced muscle degradation in response to several factors, such as disuse, glucocorticoids, obesity, and inflammation 16 , 17 , 29 , In general, muscle mass is regulated by the balance of muscle synthesis and degradation, and several factors such as aging and inactivity enhance muscle degradation to reduce muscle mass Thus, it was assumed that the effects of QG supplementation on muscle mass might be confirmed in subjects who were slightly losing muscle mass, combined with exercise which increases muscle synthesis.

Actually, participants in the present study were 50—74 years old, whose average SMI 7. Thus, we additionally conducted the subgroup analysis of the low SMI group, whose SMIs were lower than each average of men and women, respectively Supplementary Table 2.

According to the PPS analysis, significant changes were observed in muscle stiffness Supplementary Table 3 , and there were no correlations of muscle stiffness with quantity or muscular strength Supplementary Figure 2. baseline during the week intervention Supplementary Table 3 if conducting the statistical analysis for comparing before and after the intervention in each group.

Of note, the effects of QG supplementation on muscle quantity was observed only in whole-body lean mass on DXA, not in thigh muscle CSA on MRI Supplementary Table 3. In contrast, nutritional interventions may exert systemic effects on skeletal muscle, so that lean mass on DXA would be more appropriate for evaluating these effects.

In fact, many studies have shown the effects of protein supplementation combined with exercise on muscle mass using DXA 32 , and it was reported that increased dietary protein intake enhanced whole-body lean mass, but not thigh muscle CSA, in a week intervention for elderly men Nonetheless, it may be well worth noting that the increase in whole-body lean mass could be elicited by the addition of QG supplementation to even low-intensity resistance exercise, at least in individuals with lower SMIs.

Confirmatory studies with a larger sample size are needed to clarify the efficacy of QG supplementation on muscle quantity. Most previous studies used 1, mg of quercetin aglycone per day for oral administration to evaluate its physiological effects in clinical studies 34 , The QGs used in the present study are more water-soluble and have higher bioavailability, over fold compared to quercetin aglycone Regarding the difference in absorption capacity, over mg of QG may be needed to exert physiological actions similar to 1, mg of quercetin aglycone.

Of note, a recent study demonstrated increased neuromuscular efficacy by a single ingestion of mg QGs The present study showed that the combined effects of mg of QGs with low-intensity resistance exercise on muscle quantity and quality are similar to those of mg of QGs.

Therefore, supplementation with mg QGs would be enough to obtain sufficient combined effects with resistance training, at least in muscle quantity and quality, which may be physiologically relevant in terms of safety and feasibility as a supplement.

There were some limitations in the present study. First, the evaluation used by the MRI technique was only for muscle CSAs at midthigh, but not muscle volume. The relative increase in the muscle cross-sectional area i.

However, based on the previous findings, the CSA change at the central site is almost the average of overall changes. Additionally, it is unlikely that muscle belly length is substantially increased by resistance training.

Thus, we believe that the change in muscle CSA at the central site can represent that in muscle volume. Secondly, the estimative of 1-RM performance by the indirect method of 1-RM test would be likely underestimated in the elderly people However, training effect i.

We need to consider the use of direct 1-RM test for future studies to clarify the relationships between changes of muscle stiffness and performance. Conversely, the present study had some strengths. Moreover, there were no severe adverse events by both QG supplementation and exercise and no significant difference in the incidence of adverse events among groups.

Therefore, it was considered that exercise and QG supplementation were performed adequately based on the study design. Thus, it is reasonable to say that the results from the present study provided evidence that the combination of QG supplementation and exercise improved both muscle quantity and quality.

In conclusion, the combination of QG supplementation and low-intensity resistance training exercise improved the passive muscle stiffness as an index of muscle fibrosis induced by aging to a similar degree with QG supplementation of and mg.

The present study demonstrates that a combination of exercise and nutrition would be useful for improving age-related changes in muscle quantity and quality, thus preventing sarcopenia in elderly people. The studies involving human participants were reviewed and approved by the Ethics Committee of The Fukuda Clinic and Ritsumeikan University.

YO, NM, AN, TI, MN, TA, YY, and TH designed the study. YO, AN, TI, and MF conducted the clinical trial and were responsible for the exercise intervention and supplementation. NM, TA, YY, and TH were involved in the investigation of muscle quantity and quality.

YO performed statistical analysis and data interpretation with guidance from NM, TA, YY, and TH. YO wrote the manuscript. NM, TI, and TH revised the manuscript. All authors have read and agreed to the published version of the manuscript.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

This study received funding from Suntory Wellness Ltd. YO, AN, TI, and MN Were employees of Suntory Wellness Ltd. The funder had the following involvement with the study: the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. We are grateful to all laboratory members of Ritsumeikan University for assisting in the assessments, and to Tomohiro Rogi and Hiroshi Shibata of Suntory Wellness Ltd.

for giving advice on study design in this work. We would like to thank instructors from HOS Ltd. Osaka, Japan in the present study for supporting participants to attend and complete the exercise program. QG, quercetin glycoside; CSA, cross-sectional area; VL, vastus lateralis; 1-RM, 1-repetition maximum; MRI, magnetic resonance imaging; DXA, dual-energy X-ray absorptiometry; SWE, shear wave elastography; SWV, shear wave velocity; SMI, skeletal muscle mass index; PPS, per-protocol set; ANOVA, analysis of variance.

Cruz-Jentoft AJ, Sayer AA. doi: CrossRef Full Text Google Scholar. Heymsfield SB, Gonzalez MC, Lu J, Jia G, Zheng J. Skeletal muscle mass and quality: evolution of modern measurement concepts in the context of sarcopenia. Proc Nutr Soc.

PubMed Abstract CrossRef Full Text Google Scholar. Gillies AR, Lieber RL. While more research is needed before clinical conclusions can be made, evidence suggests that quercetin may play a supportive role in antioxidative status and cellular health.

It may also help support a healthy inflammatory response and post-exercise muscle recovery. Designs for Health has been dedicated to being the most trusted source for superior quality, science-based nutritional products for nearly three decades.

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