Obesity and exercise training alter inflammatory pathway skeletal muscle small extracellular vesicle microRNAs.

NEW FINDINGS: What is the central question of this study? Is 1 week of exercise training sufficient to reduce local and systemic inflammation? Do obesity and short-term concurrent aerobic and resistance exercise training alter skeletal muscle extracellular vesicle (EV) contents? What is the main finding and its importance? Obesity alters skeletal muscle small EV microRNAs targeting inflammatory and growth pathways. Exercise training alters skeletal muscle small EV microRNAs targeting inflammatory pathways, indicative of reduced inflammation. Our findings provide support for the hypotheses that EVs play a vital role in intercellular communication during health and disease and that EVs mediate many of the beneficial effects of exercise. ABSTRACT: Obesity is associated with chronic inflammation characterized by increased levels of inflammatory cytokines, whereas exercise training reduces inflammation. Small extracellular vesicles (EVs; 30-150 nm) participate in cell-to-cell communication in part through microRNA (miRNA) post-transcriptional regulation of mRNA. We examined whether obesity and concurrent aerobic and resistance exercise training alter skeletal muscle EV miRNA content and inflammatory signalling. Vastus lateralis biopsies were obtained from sedentary individuals with (OB) and without obesity (LN). Before and after 7 days of concurrent aerobic and resistance training, muscle-derived small EV miRNAs and whole-muscle mRNAs were measured. Pathway analysis revealed that obesity alters small EV miRNAs that target inflammatory (SERPINF1, death receptor and Gαi ) and growth pathways (Wnt/ß-catenin, PTEN, PI3K/AKT and IGF-1). In addition, exercise training alters small EV miRNAs in an anti-inflammatory manner, targeting the IL-10, IL-8, Toll-like receptor and nuclear factor-κB signalling pathways. In whole muscle, IL-8 mRNA was reduced by 50% and Jun mRNA by 25% after exercise training, consistent with the anti-inflammatory effects of exercise on skeletal muscle. Obesity and 7 days of concurrent exercise training differentially alter skeletal muscle-derived small EV miRNA contents targeting inflammatory and anabolic pathways.

Factors secreted from high glucose treated endothelial cells impair expansion and differentiation of human skeletal muscle satellite cells.

KEY POINTS: Cellular communication occurs between endothelial cells and skeletal muscle satellite cells and is mitogenic for both cell types under normal conditions. Skeletal muscle atrophy and endothelial cell dysfunction occur in tandem in cardiovascular disease, type II diabetes and ageing. The present study investigated how induction of endothelial cell dysfunction via high glucose treatment impacts growth and differentiation of human skeletal muscle satellite cells in vitro. Secreted factors from high glucose treated endothelial cells impaired satellite cell expansion and differentiation via decreased proliferation and dysregulation of p38 mitogen-activated protein kinase in satellite cells committed to myogenesis. These findings highlight a novel potential role for endothelial cells in the development and pathology of skeletal muscle atrophy, which is common in patients with endothelial dysfunction related pathologies. ABSTRACT: Cross-talk between endothelial cells (ECs) and skeletal muscle satellite cells (MuSC) has been identified as an important regulator of cellular functions in both cell types. In healthy conditions, EC secreted factors promote MuSC growth and differentiation. Endothelial and satellite cell dysfunction occur in tandem in many disease states; however, no data exist examining the impact of dysfunctional EC signalling on satellite cells. Therefore, the present study aimed to evaluate the effect that factors secreted from high glucose (HG) treated ECs have on the growth and differentiation of human satellite cells (HMuSC) using a conditioned medium (CM) cell culture model. Satellite cells were isolated from human skeletal muscle and grown in CM from normal or HG treated human umbilical vein ECs (HUVECs). Satellite cells grown in CM from HG treated HUVECs reduced growth (25%), differentiation (25%) and myonuclear fusion (35%). These responses were associated with increased superoxide (50%) and inflammatory cytokines (25-50%) in HG treated HUVECs and HG-CM. Decreased expansion of HG-CM treated HMuSCs was driven by a decrease in proliferation. Impaired gene expression and protein content of myogenic differentiation factors were preceded by decreased phosphorylation of p38 mitogen-activated protein kinase in HMuSC treated with CM from HG treated HUVECs. The results obtained in the present study are the first to show that factors secreted from HG treated ECs cause impairments in human muscle satellite cell growth and differentiation in vitro, highlighting endothelial cell health and secretion as a potential target for treating vascular disease-associated skeletal muscle dysfunction.

Altered formation of the iron oxide nanoparticle-biocorona due to individual variability and exercise.

Nanoparticles (NPs), introduced into a biological environment, accumulate a coating of biomolecules or biocorona (BC). Although the BC has toxicological and pharmacological consequences, the effects of inter-individual variability and exercise on NP-BC formation are unknown. We hypothesized that NPs incubated in plasma form distinct BCs between individuals, and exercise causes additional intra-individual alterations. 20 nm iron oxide (Fe3O4) NPs were incubated in pre- or post-exercise plasma ex vivo, and proteomics was utilized to evaluate BC components. Analysis demonstrated distinct BC formation between individuals, while exercise was found to enhance NP-BC complexity. Abundance differences of NP-BC proteins were determined between individuals and resulting from exercise. Differential human macrophage response was identified due to NP-BC variability. These findings demonstrate that individuals form unique BCs and that exercise influences NP-biomolecule interactions. An understanding of NP-biomolecule interactions is necessary for elucidation of mechanisms responsible for variations in human responses to NP exposures and/or nano-based therapies.