Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise

Author:

Ramos Anna E.1,Lo Claire23,Estephan Leonard E.1,Tai Yi-Yin1,Tang Ying1,Zhao Jingsi1,Sugahara Masataka4,Gorcsan John5,Brown Marcel G.3,Lieberman Daniel E.2,Chan Stephen Y.1,Baggish Aaron L.3

Affiliation:

1. Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, Pennsylvania

2. Department of Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts

3. Cardiovascular Performance Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

4. Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan

5. Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Abstract

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.

Funder

HHS | National Institutes of Health (NIH)

Amercian Heart Association

UPMC Department of Pathology Klionsky Summer Research Fellowship

Hintze Family Charitable Foundation

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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