Skeletal muscle is a heterogeneous tissue comprised of muscle fiber and mononuclear cell types that, in addition to movement, influences immunity, metabolism and cognition. We investigated the gene expression patterns of skeletal muscle cells using RNA-seq of subtype-pooled single human muscle fibers and single cell RNA-seq of mononuclear cells from human vastus lateralis, mouse quadriceps, and mouse diaphragm. We identified 11 human skeletal muscle mononuclear cell types, including two fibro-adipogenic progenitor (FAP) cell subtypes. The human FBN1+ FAP cell subtype is novel and a corresponding FBN1+ FAP cell type was also found in single cell RNA-seq analysis in mouse. Transcriptome exercise studies using bulk tissue analysis do not resolve changes in individual cell-type proportion or gene expression. The cell-type gene signatures provide the means to use computational methods to identify cell-type level changes in bulk studies. As an example, we analyzed public transcriptome data from an exercise training study and revealed significant changes in specific mononuclear cell-type proportions related to age, sex, acute exercise and training. Our single-cell expression map of skeletal muscle cell types will further the understanding of the diverse effects of exercise and the pathophysiology of muscle disease.

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).

This study provides the first insights into fast and slow muscle fiber transcriptome dynamics with lifelong endurance exercise. The fast fibers were more responsive to exercise with divergent transcriptome signatures among young exercisers (growth and metabolic), lifelong exercisers (metabolic), and old healthy nonexercisers (stress). Only lifelong exercisers had a biological response in slow fibers (metabolic). These data provide novel insights into fast and slow muscle fiber health at the molecular level with age and exercise.

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.

Declines in skeletal muscle health are a concern for astronauts on long-duration spaceflights. The current findings add to the growing body of exercise countermeasures data, suggesting that small doses of specific exercise can be beneficial for certain aspects of skeletal muscle health. This information can be used in conjunction with other components of existing exercise programs for astronauts and might translate to other areas focused on skeletal muscle health (e.g., sports medicine, rehabilitation, aging).

Muscle impairment in chronic kidney disease (CKD) contributes to decreased physical performance, frailty, and increased mortality. This proof-of-concept randomized controlled study evaluated the efficacy of a 12-week home-based, video-supervised exercise program on muscle endurance in moderate-to-severe nondialysis CKD. Thirty-two sedentary adults with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m²) were randomized (3:1) to a home exercise group (EX, n = 23) or usual care group (UC, n = 9). The primary outcome was in vivo muscle mitochondrial bioenergetics (rate of phosphocreatine recovery, k_PCr) measured using phosphorus-31 magnetic resonance spectroscopy. Secondary outcomes included 6-minute walk test (6MWT) distance (6MWD), total work, peak oxygen consumption (VO₂peak), and work efficiency obtained from cardiopulmonary exercise testing (CPET). Other outcomes were body composition and plasma cytokines. Within- and between-group differences were analyzed using linear mixed models (LMMs). Mean (SD) ages were 62.6 (10.8) years in EX and 67.2 (8.2) in UC. Mean eGFRs were 35.0 (12.6) and 32.3 (12.0) ml/min per 1.73 m², respectively. No serious adverse events occurred; 90.5% of EX completed ≥ 75% of sessions. Compared with UC, EX significantly increased k_PCr (0.20/min, 95% confidence interval [CI]: 0.05–0.35, P = 0.01), total work (5.03 kJ, 95% CI: 1.25–8.80, P = 0.007), and 6MWD (39.1 m, 95% CI: 7.1–71.1, P = 0.014) while preserving fat-free mass (2.3 kg, 95% CI: 0.49–4.1, P = 0.024) and marginally decreasing fat mass (−2.22 kg, 95% CI: −4.7 to 0.27, P = 0.1) . Interleukin (IL)-8 concentration differed between groups (effect size: −1.16, 95% CI: −2.4 to −0.04, P = 0.016). Work efficiency, VO₂peak, and other cytokines showed no significant differences between groups. Home-based, video-supervised exercise is feasible, improves muscle oxidative capacity and endurance, offering a strategy to mitigate functional decline in moderate-to-severe nondialysis CKD.