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Effect of dietary n-3 PUFA supplementation on the muscle transcriptome in older adults.

ABSTRACT: Dietary fish oil-derived n-3 PUFA supplementation can increase muscle mass, reduce oxygen demand during physical activity, and improve physical function (muscle strength and power, and endurance) in people. The results from several studies conducted in animals suggest that the anabolic and performance-enhancing effects of n-3 PUFA are at least in part transcriptionally regulated. The effect of n-3 PUFA therapy on the muscle transcriptome in people is unknown. In this study, we used muscle biopsy samples collected during a recently completed randomized controlled trial that found that n-3 PUFA therapy increased muscle mass and function in older adults to provide a comprehensive assessment of the effect of n-3 PUFA therapy on the skeletal muscle gene expression profile in these people. Using the microarray technique, we found that several pathways involved in regulating mitochondrial function and extracellular matrix organization were increased and pathways related to calpain- and ubiquitin-mediated proteolysis and inhibition of the key anabolic regulator mTOR were decreased by n-3 PUFA therapy. However, the effect of n-3 PUFA therapy on the expression of individual genes involved in regulating mitochondrial function and muscle growth, assessed by quantitative RT-PCR, was very small. These data suggest that n-3 PUFA therapy results in small but coordinated changes in the muscle transcriptome that may help explain the n-3 PUFA-induced improvements in muscle mass and function.

SUBMITTER: Yoshino J

PROVIDER: S-EPMC4908485 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Effect of dietary n-3 PUFA supplementation on the muscle transcriptome in older adults.

Yoshino Jun J Smith Gordon I GI Kelly Shannon C SC Julliand Sophie S Reeds Dominic N DN Mittendorfer Bettina B

Physiological reports 20160601 11

Dietary fish oil-derived n-3 PUFA supplementation can increase muscle mass, reduce oxygen demand during physical activity, and improve physical function (muscle strength and power, and endurance) in people. The results from several studies conducted in animals suggest that the anabolic and performance-enhancing effects of n-3 PUFA are at least in part transcriptionally regulated. The effect of n-3 PUFA therapy on the muscle transcriptome in people is unknown. In this study, we used muscle biopsy ...[more]

PMID: 27252251

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Project description:ObjectiveVitamin D deficiency is common among older adults and has been linked to muscle weakness. Vitamin D supplementation has been proposed as a strategy to improve muscle function in older adults. The aim of this study was to investigate the effect of calcifediol (25-hydroxycholecalciferol) on whole genome gene expression in skeletal muscle of vitamin D deficient frail older adults.MethodsA double-blind placebo-controlled trial was conducted in vitamin D deficient frail older adults (aged above 65), characterized by blood 25-hydroxycholecalciferol concentrations between 20 and 50 nmol/L. Subjects were randomized across the placebo group and the calcifediol group (10 μg per day). Muscle biopsies were obtained before and after 6 months of calcifediol (n = 10) or placebo (n = 12) supplementation and subjected to whole genome gene expression profiling using Affymetrix HuGene 2.1ST arrays.ResultsExpression of the vitamin D receptor gene was virtually undetectable in human skeletal muscle biopsies, with Ct values exceeding 30. Blood 25-hydroxycholecalciferol levels were significantly higher after calcifediol supplementation (87.3 ± 20.6 nmol/L) than after placebo (43.8 ± 14.1 nmol/L). No significant difference between treatment groups was observed on strength outcomes. The whole transcriptome effects of calcifediol and placebo were very weak, as indicated by the fact that correcting for multiple testing using false discovery rate did not yield any differentially expressed genes using any reasonable cut-offs (all q-values ~ 1). P-values were uniformly distributed across all genes, suggesting that low p-values are likely to be false positives. Partial least squares-discriminant analysis and principle component analysis was unable to separate treatment groups.ConclusionCalcifediol supplementation did not significantly affect the skeletal muscle transcriptome in frail older adults. Our findings indicate that vitamin D supplementation has no effects on skeletal muscle gene expression, suggesting that skeletal muscle may not be a direct target of vitamin D in older adults.Trial registrationThis study was registered at clinicaltrials.gov as NCT02349282 on January 28, 2015.

Project description:ImportanceAging is associated with a decline in mitochondrial function and reduced exercise capacity. Urolithin A is a natural gut microbiome-derived food metabolite that has been shown to stimulate mitophagy and improve muscle function in older animals and to induce mitochondrial gene expression in older humans.ObjectiveTo investigate whether oral administration of urolithin A improved the 6-minute walk distance, muscle endurance in hand and leg muscles, and biomarkers associated with mitochondrial and cellular health.Design, setting, and participantsThis double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 years was conducted at a medical center and a cancer research center in Seattle, Washington, from March 1, 2018, to July 30, 2020. Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 months, and 4 months. Six-minute walk distance and maximal ATP production were assessed using magnetic resonance spectroscopy at baseline and at the end of study at 4 months. The analysis used an intention-to-treat approach.InterventionsParticipants were randomized to receive daily oral supplementation with either 1000 mg urolithin A or placebo for 4 months.Main outcomes and measuresThe primary end point was change from baseline in the 6-minute walk distance and change from baseline to 4 months in maximal ATP production in the hand skeletal muscle. The secondary end points were change in muscle endurance of 2 skeletal muscles (tibialis anterior [TA] in the leg and first dorsal interosseus [FDI] in the hand). Cellular health biomarkers were investigated via plasma metabolomics. Adverse events were recorded and compared between the 2 groups during the intervention period.ResultsA total of 66 participants were randomized to either the urolithin A (n = 33) or the placebo (n = 33) intervention group. These participants had a mean (SD) age of 71.7 (4.94) years, were predominantly women (50 [75.8%]), and were all White individuals. Urolithin A, compared with placebo, significantly improved muscle endurance (ie, increase in the number of muscle contractions until fatigue from baseline) in the FDI and TA at 2 months (urolithin A: FDI, 95.3 [115.5] and TA, 41.4 [65.5]; placebo: FDI, 11.6 [147.4] and TA, 5.7 [127.1]). Plasma levels of several acylcarnitines, ceramides, and C-reactive protein were decreased by urolithin A, compared with placebo, at 4 months (baseline vs 4 mo: urolithin A, 2.14 [2.15] vs 2.07 [1.46]; placebo, 2.17 [2.52] vs 2.65 [1.86]). The mean (SD) increase from baseline in the 6-minute walk distance was 60.8 (67.2) m in the urolithin A group and 42.5 (73.3) m in the placebo group. The mean (SD) change from baseline to 4 months in maximal ATP production in the FDI was 0.07 (0.23) mM/s in the urolithin A group and 0.06 (0.20) mM/s in the placebo group; for the TA, it was -0.03 (0.10) mM/s in the urolithin A group and 0.03 (0.10) mM/s in the placebo group. These results showed no significant improvement with urolithin A supplementation compared with placebo. No statistical differences in adverse events were observed between the 2 groups.Conclusions and relevanceThis randomized clinical trial found that urolithin A supplementation was safe and well tolerated in the assessed population. Although the improvements in the 6-minute walk distance and maximal ATP production in the hand muscle were not significant in the urolithin A group vs the placebo group, long-term urolithin A supplementation was beneficial for muscle endurance and plasma biomarkers, suggesting that urolithin A may counteract age-associated muscle decline; however, future work is needed to confirm this finding.Trial registrationClinicalTrials.gov Identifier: NCT03283462.

Dataset Information

Effect of dietary n-3 PUFA supplementation on the muscle transcriptome in older adults.

Publications

Effect of dietary n-3 PUFA supplementation on the muscle transcriptome in older adults.

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