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Changes in the transcriptome of circulating neutrophils and skeletal muscle in response to endurance exercise

ABSTRACT: Analysis of the changes in the transcriptome of circulating neutrophils and skeletal muscle from standardized resting conditions (baseline; pre-EXTRI) to 3, 48 and 96 hours after an experimental exercise trial (EXTRI; 1 hour of cycling followed by 1 hours of running) in 8 healthy, endurance-trained, male subjects. It was hypothesized that the time-course dependent transcriptomic changes would reflect the molecular and signalling mechanisms by which neutrophils regulate and counter-regulate inflammation, and by which skeletal muscle responds, regenerates, and phenotypically adapts to intense, prolonged exercise involving muscle damage. Results provide an important insight in the signalling pathways underlying the transcriptional activation and priming of circulatory neutrophils in response to physiological stress, in particular muscle-derived damage-associated molecular patterns. Furthermore, the study provides novel data on the skeletal muscle transcriptome beyond 48 hours after strenuous endurance exercise, and indicates important muscular remodelling processes at 96 hours post-EXTRI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43856 | GEO | 2013/01/30

SECONDARY ACCESSION(S): PRJNA187923

REPOSITORIES: GEO

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Project description:Preclinical models of type 1 diabetes mellitus exhibit marked declines in skeletal muscle health including significant impairments in muscle repair. The present study investigated, for the first time, whether muscle repair was altered in young adults with uncomplicated type 1 diabetes (T1D) following damaging exercise.In this cohort study, eighteen physically-active young adults (M=22.1, SEM=0.9 years) with T1D (n, male/female=4/5; MHbA1c= 58, SEMHbA1c=5.9 mmol/mol) and without T1D (n, male/female=4/5) performed 300 unilateral eccentric contractions (90°s-1) of the knee extensors. Prior to exercise, at 48-hours and at 96-hours after exercise, participants gave a venous blood sample and vastus lateralis biopsy and performed a maximal voluntary isometric knee extension. Skeletal muscle extracellular matrix content, and satellite cell content/proliferation were assessed by immunofluorescence. Transmission electron microscopy was used to quantify ultrastructural damage.Maximal isometric strength was comparable between T1D and their sex-matched control group prior to exercise for both sexes. Immediately following damaging exercise, strength was decreased in both groups but there was a moderate effect size for lower strength during recovery in the T1D group at both 48-hours and 96-hours. Serum creatine kinase, an indicator of muscle damage, was moderately higher in T1D participants compared to controls at rest, and exhibited a small elevation 96-hours after exercise. Immunofluorescence analyses showed satellite cell content was lower at all timepoints in those with type 1 diabetes. T1D participants demonstrated a moderate delay in satellite cell proliferation (as assessed by Pax7+/Ki67+ nuclei counts) after exercise, reaching peak levels of proliferation 48-hours after control participants. Despite these differences, those with T1D did not exhibit greater ultrastructural muscle damage than controls as assessed by electron microscopy. Finally, a transcriptomic investigation of T1D muscle revealed several networks of dysregulated genes involving RNA translation as well as mitochondrial respiration function, providing potential explanations for previous observations of mitochondrial dysfunction in similar T1D cohorts. Our novel findings indicate that skeletal muscle from physically active, young adults with moderately controlled T1D may have a reduced ability to handle, and repair from, damaging exercise. While larger cohort studies are clearly needed, these results suggest that those with T1D may require longer recovery times following damaging exercise.

Project description:Protein-leucine supplement ingestion following strenuous endurance exercise accentuates skeletal-muscle protein synthesis and adaptive molecular responses, but the underlying transcriptome is uncharacterized. In a randomized single-blind triple-crossover design, 12 trained men completed 100 min of high-intensity cycling then ingested either 70/15/180/30g protein/leucine/carbohydrate/fat (15LEU), 23/5/180/30g (5LEU) or 0/0/274/30g (CON) beverages during the first 90 min of a 240-min recovery period. Vastus lateralis muscle samples (30 and 240-min post-exercise) underwent transcriptome analysis by microarray followed by bioinformatic analysis. Gene expression was regulated by Protein-leucine in a dose-dependent manner impacting the inflammatory response, muscle growth and development. At 30 min, 15LEU and 5LEU vs. CON activated transcriptome networks with geneset functions involving cell-cycle arrest (Z-score 2.0-2.7; P<0.01), leukocyte maturation (1.7; P=0.007), cell viability (2.4; P=0.005), promyogenic networks encompassing myocyte differentiation and myogenin (MYOD1, MYOG), and a proteinaceous extracellular matrix, adhesion, and development programme correlated with plasma lysine, arginine, tyrosine, taurine, glutamic acid, and asparagine concentrations. High protein-leucine dose (15LEU-5LEU) activated an IL1b-centered proinflammatory network and leukocyte migration, differentiation, and survival functions (2.0-2.6; <0.001). By 240 min, the protein-leucine transcriptome was anti-inflammatory and promyogenic (IL-6, NF-kÎ², SMAD, STAT3 network inhibition), with overrepresented functions including decreased leukocyte migration and connective tissue development (-1.8-2.4; P<0.01), increased apoptosis of myeloid and muscle cells (2.2-3.0; P<0.002) and cell metabolism (2.0-2.4; P<0.01). The analysis suggests protein-leucine ingestion modulates inflammatory-myogenic regenerative processes during skeletal muscle recovery from endurance exercise. Further cellular and translational research is warranted to validate amino acid-mediated myeloid and myocellular mechanisms within skeletal-muscle functional plasticity. Total RNA obtained from isolated skeletal muscles

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Changes in the transcriptome of circulating neutrophils and skeletal muscle in response to endurance exercise

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