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).

Aging and poor diet are independent risk factors for heart disease, but the impact of high-sucrose (HS) consumption in the aging heart is understudied. Aging leads to impairments in mitochondrial function that result in muscle dysfunction (e.g., cardiac remodeling and sarcopenia). We tested whether HS diet (60%kcal sucrose) would accelerate muscle dysfunction in 24-month-old male CB6F1 mice. By week 1 on HS diet, mice developed significant cardiac hypertrophy compared to age-matched chow-fed controls. The increased weight of the heart persisted throughout the 4-week treatment, while body weight and strength declined more rapidly than controls. We then tested whether HS diet could worsen cardiac dysfunction in old mice and if the mitochondrial-targeted drug, elamipretide (ELAM), could prevent the diet-induced effect. Old and young mice were treated with either ELAM or saline as a control for 2 weeks, and provided with HS diet or chow on the last week. As demonstrated in the previous experiment, old mice had age-related cardiac hypertrophy that worsened after one week on HS and was prevented by ELAM treatment, while the HS diet had no detectable effect on hypertrophy in the young mice. As expected, mitochondrial respiration and reactive oxygen species (ROS) production were altered by age, but were not significantly affected by HS diet or ELAM. Our findings highlight the vulnerability of the aged heart to HS diet that can be prevented by systemic targeting of the mitochondria with ELAM.

Key Points: Nicotinamide riboside and coenzyme Q10 supplementation showed distinct beneficial effects on whole-blood transcriptome, inflammatory cytokines, and oxidative stress. Nicotinamide riboside treatment altered the expression of genes associated with metabolism and immune response coinciding with a decrease in markers of oxidative stress. Coenzyme Q10 supplementation altered genes associated with lipid metabolism coinciding with reductions in markers of oxidative stress and inflammatory cytokines. Background: Mitochondria-driven oxidative/redox stress and inflammation play a major role in CKD pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. Methods: We conducted a pilot, randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/d of coenzyme Q10 (CoQ10) or 1000 mg/d of nicotinamide riboside (NR) supplementation with placebo in 25 patients with moderate-to-severe CKD (eGFR <60 ml/min per 1.73 m²). We assessed changes in blood transcriptome using 3′-Tag-Seq gene expression profiling and changes in prespecified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. Results: The (mean±SD) age, eGFR, and body mass index of the participants were 61±11 years, 37±9 ml/min per 1.73 m², and 28±5 kg/m², respectively. Of the participants, 16% had diabetes and 40% were female. Compared with placebo, NR-mediated transcriptomic changes were enriched in gene ontology terms associated with carbohydrate/lipid metabolism and immune signaling, whereas CoQ10 changes were enriched in immune/stress response and lipid metabolism gene ontology terms. NR increased plasma IL-2 (estimated difference, 0.32; 95% confidence interval [CI], 0.14 to 0.49 pg/ml), and CoQ10 decreased both IL-13 (estimated difference, −0.12; 95% CI, −0.24 to −0.01 pg/ml) and C-reactive protein (estimated difference, −0.11; 95% CI, −0.22 to 0.00 mg/dl) compared with placebo. Both NR and CoQ10 reduced five-series F2-isoprostanes (estimated difference, −0.16 and −0.11 pg/ml, respectively; P < 0.05 for both). NR, but not CoQ10, increased the Bioenergetic Health Index (estimated difference, 0.29; 95% CI, 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52; 95% CI, 0.04 to 7 pmol/min per 10,000 cells) in monocytes. Conclusions: Six weeks of NR and CoQ10 improved markers of oxidative stress, inflammation, and cell bioenergetics in patients with moderate-to-severe CKD. Clinical Trial registry name and registration number: NCT03579693.

Background: Eccentric contractions induce muscle damage (EIMD) that compromises muscle function. Poor recovery from EIMD has been suggested to be a contributor to the decline in muscle function evident in sarcopenia, but it is unclear which aspects of muscle function are more susceptible to disruption by EIMD in old versus young muscle. The purpose of this study was to determine the extent of impairment in contractile function (force, fatigue, tetanus and twitch kinetics) during the recovery from EIMD in VO mice compared to young adult (YA).Methods: Male CB6F1 were obtained from National Institure of Aging colony. VO mice were 29–31 months of age, and YA mice were 7–9 months of age. The plantarflexor muscles were subjected to 20 eccentric contractions in vivo to induce injury (EIMD). Changes in tetanic force and kinetics were assessed before EIMD, immediately after EIMD and 3 days after EIMD (3d‐EIMD). Force–frequency and rates of fatigue were assessed 3d‐EIMD and compared with baseline. Histological analysis was conducted in injured and non‐injured contralateral gastrocnemius muscle.Results: There was a greater loss in isometric tetanic force immediately following EIMD in VO compared with YA (−31.6% ± 10.4 vs. −21.7% ± 6.0, P < 0.05). At 3d‐EIMD, the rate of contraction of tetanus began to recover in VO, but not in YA (20.8% vs. −6.8%, P < 0.05), whereas the extent of recovery of force tended to be greater in VO than YA (39.3% vs. 17.1%, P = 0.08) when compared with tetanic function immediately after injury. Compared with function pre‐injury (baseline), VO and YA had similar deficits in tetanic force (−7.3% ± 5.3 vs. ‐9.2% ± 6.0, respectively) and kinetics at Day 3. Twitch kinetics (rate of relaxation) recovered faster in VO compared with YA. The rate of muscle fatigue was similar to baseline values, with VO continuing to be more fatigue resistant than YA 3d‐EIMD. There were no detectable differences in muscle mass or myofibre cross‐sectional area despite continued deficits in force following EIMD in either age group.Conclusions: Despite clear functional deficits and greater susceptibility to injury, aged sarcopenic muscle exhibited a similar ability to recover contractile function to younger muscle following EIMD. In addition, neither age group showed accelerated muscle fatigue in the recovery phase after EIMD; thus, sarcopenic mouse muscles do not appear to be more susceptible to long‐term functional impairment than young healthy muscles.

Peripheral mononuclear cells (PBMCs) exhibit robust changes in mitochondrial respiratory capacity in response to health and disease. While these ... Jove