Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs. NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.
Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise. Abbreviations CAD Coronary artery disease CVD Cardiovascular disease GWAS Genome wide association study HR Heart rate pQTL Protein quantitative trait locus VȮ 2 Oxygen consumption VT Ventilatory threshold Physical activity, including structured exercise, is associated with numerous health benefits including enhanced cognition 1 , reduction in cardiovascular disease (CVD) 2 , improved cancer outcomes 3 , and decreased mortality 4. Cardiovascular benefits from exercise training have been ascribed to improvements in lipid profiles, blood
Whole-body alanine kinetics were studied using continuous infusions of [15N]-, [3,3,3-2H3]-, [1-13C]-, and [3-13C]alanine tracers in healthy male subjects in the postabsorptive state. Alanine kinetics were highly dependent on the choice of isotopically labeled alanine. Highest rates of alanine flux (mean +/- SE) were obtained with the [3,3,3-2H3]alanine (474 +/- 41 mumol X kg-1 X h-1). [1-13C]- and [3-13C]alanine tracers gave intermediate values (297 +/- 12 and 317 +/- 22 mumol X kg-1 X h-1, respectively). The slowest rates of alanine turnover were measured with [15N]alanine (226 +/- 7 mumol X kg-1 X h-1). These results emphasize the heterogeneous metabolism of different portions of the alanine molecule and the importance of choosing an appropriate alanine tracer for studying different aspects of alanine metabolism.
Aerobic exercise confers myriad benefits to human health but the mechanism by which it does so remain incompletely understood. We hypothesize that exercise works in part through circulating protein signaling. Healthy adult men (n, 12) participated in treadmill running sessions at both low (6 mph) and high intensity (maximal effort). We used pre- and post-exercise plasma and a high-throughput aptamer-based assay (SomaScan) to examine the acute impact of exercise on the plasma proteome. Acute aerobic exercise consistently alters the resting plasma proteome in an intensity-dependent fashion. Of 1,305 proteins assayed 184 (14%) and 598 (46%) change at low and high intensity respectively (FDR p < 0.05). 159 protein species (12%) are common to both intensities. Gene ontology analysis revealed enrichment of pathways associated with leukocyte chemotaxis and chylomicron metabolism at low intensity and Wnt signaling, neuronal axonogenesis, and nitric oxide metabolism pathways at high intensity. We used human sequencing data from the GTEX Consortium (Broad, Cambridge MA) to computationally infer the sources of increasing proteins and found major contributions from the cardiovascular, gastrointestinal, and nervous systems. We identified 43 cis-SNPs that approximate the upregulated proteomic response to acute exercise and used Mendelian randomization to infer a causal relationship between the exercise proteome and decreased muscle wasting in a UK Biobank cohort. Although guidelines present low and high intensity exercise as equivalent alternatives for health, these data suggest that distinct exercise intensities might offer common and distinct exercise benefits.
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