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Acute Nutritional Ketosis During Early Recovery from Exercise Does Not Affect Skeletal Muscle Transcriptomic Response

ABSTRACT: Purpose: Recent research suggests that Ketone monoester (KME) supplementation may enhance skeletal muscle adaptation to exercise, possibly modulated be an increased secretion of erythropoietin (EPO) and increased muscle glycogen resynthesis, but the precise molecular pathways driving the response remain uncertain. Therefore, we aimed at characterising the modulation of skeletal muscle by KME through a genome-wide characterisation of the transcriptome early post-exercise. Methods: Following a randomized, double-blind, crossover design, recreationally active men [n= 9; age: 26 ± 5 (means ± SD); height: 1.80 ± 0.07 m; body mass: 80 ± 9 kg; V̇O2max: 47 ± 4 mL·kg-1·min-1]) completed two experimental trials where they ingested either 1.25 g/kg of KME (>96% (R)-3-hydroxybutyl (R)-3-hydroxybutyrate) or a taste-matched placebo (PLA) drink around exercise (90-min cycling at 60% of VO2max) in standardised conditions. . Venous blood samples were taken throughout baseline, exercise and recovery, and skeletal muscle biopsies were taken at baseline and 3-h post exercise. Results: KME intake elevated serum ßHB concentrations post-exercise to 3.3 ± 0.5 mM and remained elevated levels during recovery (range: ~4.0–4.7 mM). Remarkably, there was no marked upregulation or downregulation of differentially expressed genes at 3-h post-exercise with KME supplementation compared to PLA. Although, baseline serum EPO levels were higher in PLA (12.8 ± 3.9 IU/L) compared to KME (10.1 ± 5.7 IU/L) and remained slightly higher in PLA throughout recovery, there was not significant difference between conditions. Pre- and post- exercise muscle glycogen concentrate were similar between conditions (KME PRE: 501 ± 118 mmol/kg, KME POST, 284 ± 117 mmol/kg, PLA PRE: 492 ± 102 mmol/kg, PLA POST: 282 ± 184 mmol/kg). Conclusions: Our findings indicate that despite a sustained post-exercise increase in serum ßHB concentrations, KME supplementation did not induce transcriptional changes in skeletal muscle. Additionally, in contrast to previous studies, KME did not affect glycogen concentrations or serum EPO levels during the first 3-hours post-exercise.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292369 | GEO | 2025/11/18

REPOSITORIES: GEO

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Project description:The obese, insulin resistant state is characterized by impairments in lipid metabolism. Dietary polyphenols might improve these deteriorations. We have previously shown that 3-days supplementation of combined Epigallocatechin-gallate and Resveratrol (E+R) increased energy expenditure, which was accompanied by improved metabolic flexibility after a high-fat mixed-meal (HFMM) in men. The present study aimed to investigate whether these short-term effects translate into longer-term improvement of insulin sensitivity and lipid metabolism. In this randomized, double-blind study, 42 overweight subjects (21 male, 38Â±2 yrs, BMI 29.7Â±0.5 kg/m2, HOMA-IR 2.1Â±0.2) received either E+R (300 and 80 mg/d, respectively) or placebo (PLA) for 12 weeks (3 months). Before (t0) and after (t3) intervention, tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with stable isotope infusion. Fasting and postprandial (HFMM) lipid metabolism was assessed using indirect calorimetry and blood sampling. Adipose tissue and skeletal muscle lipolysis was measured using microdialysis in men and skeletal muscle biopsies were collected to assess mitochondrial function and gene expression alterations via microarray analysis. E+R supplementation increased fasting (P=0.06) and postprandial (P=0.03) fat oxidation but did not alter energy expenditure compared to PLA. This was accompanied by an E+R-induced increase in oxidative capacity in permeabilized muscle fibers (p<0.05). Moreover, E+R supplementation attenuated the increase in plasma triacylglycerol concentration that was observed in the PLA group (AUC, p<0.05), and tended to decrease visceral fat mass (P=0.09). Finally, insulin-stimulated glucose disposal and suppression of endogenous glucose production were not affected by E+R supplementation. 12 weeks E+R supplementation increased whole-body fat oxidation and skeletal muscle oxidative capacity, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. To identify pathways that may underlie the E+R-induced improvement of skeletal muscle mitochondrial capacity, we performed microarray analysis on skeletal muscle biopsies (vastus lateralis muscle), collected before and after 12-weeks E+R or PLA treatment. Gene Set Enrichment Analysis (GSEA) indicated that the most upregulated pathways after E+R supplementation were related to the citric acid cycle and respiratory electron transport chain, while pathways related to carbohydrate metabolism were upregulated in the PLA group. In this randomized, double-blind placebo-controlled, parallel intervention trial, subjects received either a combination of E+R supplements (INTV, 282 mg/d and 80 mg/d, respectively) or placebo (PLA, partly hydrolyzed microcrystalline cellulose-filled capsules) for a period of 12 weeks (3 months) to assess effects of E+R supplementation on tissue-specific insulin sensitivity (primary outcomes) and fasting and postprandial substrate metabolism (secondary outcomes). Skeletal muscle (m. vastus lateralis) biopsies were taken under local anesthesia during fasting conditions before (t0) and after the 12-weeks (t3) intervention period. Extraxted RNA was hybridized on HTA 2.0 Affymetrix arrays and microarray analysis was performed on paired sample sets for 27 subjects (p, PLA n = 14; E+R n = 13).

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Acute Nutritional Ketosis During Early Recovery from Exercise Does Not Affect Skeletal Muscle Transcriptomic Response

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