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      Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease

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          Abstract

          Background

          Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.

          Methods

          We conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m 2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO 2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.

          Results

          Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m 2. Compared with placebo, we found no differences in VO 2 peak ( P = 0.30, 0.17), total work ( P = 0.47, 0.77), and total work efficiency ( P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO 2 at 30 W ( P = 0.03) and VO 2 at 60 W ( P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment ( P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD + and NADP + as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.

          Conclusions

          Six weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO 2 peak or total work efficiency.

          Trial registration

          ClinicalTrials.gov NCT03579693.

          Funding

          National Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).

          Abstract

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          Most cited references76

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          The Physical Activity Guidelines for Americans

          Approximately 80% of US adults and adolescents are insufficiently active. Physical activity fosters normal growth and development and can make people feel, function, and sleep better and reduce risk of many chronic diseases.
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            NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus.

            NAD(+) has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD(+) metabolism revived interest in NAD(+)-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.
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              NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.

              Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its effect on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the mdx (C57BL/10ScSn-Dmd(mdx)/J) mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs and melanocyte SCs and increases mouse life span. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve life span in mammals.
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                Author and article information

                Contributors
                Journal
                JCI Insight
                JCI Insight
                JCI Insight
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                8 June 2023
                8 June 2023
                8 June 2023
                : 8
                : 11
                : e167274
                Affiliations
                [1 ]Department of Medicine, Division of Nephrology, UCD, Davis, California, USA.
                [2 ]Kinesiology Department, California State University, Sacramento, California, USA.
                [3 ]Department of Radiology, University of Washington, Seattle, Washington, USA.
                [4 ]Department of Internal Medicine, Division of Cardiovascular Medicine, UCD, Davis, California, USA.
                [5 ]Department of Medicine, University of Washington, Seattle, Washington, USA.
                [6 ]Obesity and Metabolism Research Unit, Western Human Nutrition Research Center, USDA, ARS, Davis, California, USA.
                [7 ]Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
                [8 ]Department of Biostatistics, UCD, Davis, California, USA.
                [9 ]Department of Medicine, Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington, USA.
                [10 ]School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
                Author notes
                Address correspondence to: Baback Roshanravan, 451 Health Sciences Drive, Genome Biomedical Sciences Facility, Suite 5321, Davis, California 95616, USA. Phone: 530.754.8258; Email: broshanr@ 123456ucdavis.edu .
                Author information
                http://orcid.org/0000-0002-0636-8303
                http://orcid.org/0000-0002-2833-6492
                http://orcid.org/0000-0002-6903-6031
                http://orcid.org/0000-0003-0484-4385
                http://orcid.org/0000-0002-0766-3195
                http://orcid.org/0000-0001-6761-5606
                http://orcid.org/0000-0002-3319-1224
                http://orcid.org/0000-0003-1571-7592
                http://orcid.org/0000-0003-1320-0442
                Article
                167274
                10.1172/jci.insight.167274
                10393227
                37159264
                18af01ac-5d19-43cc-bfbb-0a3ee77f4401
                © 2023 Ahmadi et al.

                This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 November 2022
                : 3 May 2023
                Categories
                Clinical Medicine

                clinical trials,nephrology,chronic kidney disease,mitochondria,skeletal muscle

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