Project description:Exercise improves cardiometabolic and vascular function, though mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing (RNA-seq) in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., y-RNAs, t-RNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. Circulating ex-RNAs altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., y-RNAs) is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.
Project description:Exercise triggers skeletal muscle signalling pathways that modulate the release of circulating factors to cause systemic health benefits. Understanding these mechanisms could lead to better strategies for treating cardiometabolic diseases. We previously showed that acute exercise induces >1000 changes in protein phosphorylation in human muscle. Here we employed a strategy to deconvolute this network by analysing phosphoproteomes of rat L6 myotubes treated with small molecules that mimic different aspects of exercise signalling. Bioinformatics suggested that combining β-adrenergic and calcium agonists would yield a phosphoproteome most closely resembling exercise. Experimental analysis supported this but also revealed a surprising divergence in signalling from that observed with either drug alone. Dual stimulation promoted multisite phosphorylation of SERBP1, a regulator of Serpine1 mRNA stability, a pro-thrombotic fibrotic secreted protein. Secretomic analysis of L6 myotubes treated with β-adrenergic and calcium agonists revealed a significant decrease in SERPINE1 secretion and other deleterious secretory factors. This provides a novel approach to dissect the beneficial effects of exercise and demonstrates an underappreciated effect of exercise to reduce the circulating levels of certain factors, providing new insights into exercise benefits and their therapeutic potential.
Project description:Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered that “runner” plasma, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU), a central protein for the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in an Alzheimer’s disease mouse model. Cognitively impaired patients participating in structured exercise for 6 months had higher plasma clusterin levels. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans engaging in exercise.
Project description:Objective: Physical exercise and vitamin E are considered effective treatments of nonalcoholic fatty liver and other metabolic diseases. However, vitamin E has also been shown to interfere with the adaptation to exercise training, in particular for the skeletal muscle. Here, we studied the hypothesis that vitamin E also interferes with the metabolic adaptation of the liver to acute exercise. Methods: Male C57BL6/N mice were fed either control or vitamin E (α-tocopherol)- supplemented antioxidant diet during four weeks before being subjected to a non-exhaustive treadmill run. We assessed the acute transcriptional response of the liver as well as plasma corticosterone and free fatty acid (FFA) concentrations and monitored respiration in the exercising mice. Results: Vitamin E counteracted exercise-induced hepatic inflammation and altered the metabolic adaptation of the liver on the level of gene transcription. Vitamin E interfered with the upregulation of key metabolic regulators and caused a paradoxical increase in transcripts involved in lipid and cholesterol synthesis, processes negatively regulated by FFA and usually suspended during physical exercise. Whole-body energy consumption as well as corticosterone levels and signalling were similar, arguing against acute differences in fatty acid oxidation or glucocorticoid action. Conclusions: Our results show that vitamin E supplementation alters the inflammatory and transcriptional response of the liver to physical exercise. These effects of vitamin E could, on the long run, result in an impaired adaptation of the liver to physical exercise. Since exercise is clearly beneficial for general health and in reducing inflammation and dyslipidemia in nonalcoholic fatty liver disease, the interference of vitamin E with these processes may speak for a cautious use as dietary supplement.
Project description:Physical exercise seems universally beneficial to human and animal health, slowing cognitive aging and neurodegeneration. Cognitive benefits are tied to increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms mediating these effects. We discovered “runner” plasma, collected from voluntarily running mice, infused into sedentary mice recapitulates the cellular and functional benefits of exercise on the adult brain. Importantly, runner plasma reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a striking increase in complement cascade inhibitors including clusterin (CLU), which is facilitating the anti-inflammatory effects of runner plasma. Intravenously injected CLU strongly binds to brain endothelial cells reducing their inflammatory gene expression in an acute model of brain inflammation and in Alzheimer’s disease model mice. Cognitively impaired patients participating in structured exercise for 6 months showed improved cognition and higher plasma clusterin levels. These findings demonstrate the existence of anti-inflammatory “exercise factors” that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans engaging in exercise.
Project description:Gene expression data at rest and immediately post 30 min submaximal exercise in 3 month and 16 month old male rats, some of which were sedentary (SED), had access to a physical activity box twice weekly (PA) and some of which had daily access to a running wheel (EX). We used microarrays to detail global gene expression underlying select health-related phenotypes and identified differentially expressed genes among the three groups. Young (3 month) and old (16 month) male rats were separated into three different groups: Sedentary (SED), twice-weekly physical activity (PA), and regular exercise (EX). Animals were sacrificed either at rest or after 30 min of sub maximal exercise. Then, a portion of cardiac tissue was collected for RNA extraction and hybridization on Affymetrix microarrays.