Exercise provides numerous salutary effects, but our understanding of how these occur is limited. To gain a clearer picture of exercise-induced metabolic responses, we have developed comprehensive plasma metabolite signatures by using mass spectrometry to measure over 200 metabolites before and after exercise. We identified plasma indicators of glycogenolysis (glucose-6-phosphate), tricarboxylic acid (TCA) cycle span 2 expansion (succinate, malate, and * To whom correspondence should be addressed Corresponding authors Robert E. Gerszten, MD Cardiology Division and Center for Immunology & Inflammatory Diseases Massachusetts General Hospital, Room 8307 149 13th Street Charlestown, MA 02129 rgerszten@partners.org Gregory D. Lewis, MD Cardiology Division Massachusetts General Hospital, GRB 800 55 Fruit Street, Boston, MA 02114 glewis@partners.org. Authors contributions: G.D.L conceived the study, designed the experiments, performed primary data analysis and wrote the manuscript. M.J.W. led the effort to recruit and phenotype marathon subjects, L.F. and M.M. recruited subjects, processed samples, and assisted with experimental design. Z.A. and G.C.R. designed and performed the gene expression profiling experiments, A.S., E.Y., X.S., A.A., S.A.C. and C.B.C. developed the metabolic profiling platform, performed mass spectrometry experiments, and analyzed the data, S.C., E.L.M, T.W., and R.S.V. designed experiments and analyzed data from the Framingham Heart Study cohort, R.D. and F.P.R. assisted with statistical analysis and constructed the metabolite interrelatedness dendrogram, E.P.R. contributed to mass spectrometry data analysis and helped to write the manuscript, D.M.S. and M.J.S. contributed to the cardiopulmonary exercise testing metabolic profiling experiment, M.S.S. helped to conceive and design the exercise treadmill testing studies and assisted in data interpretation and in writing the manuscript, R.E.G. conceived of the study, designed experiments, analyzed data, and wrote the manuscript. Competing interests:The authors declare that they have no competing interests. NIH Public Access Author ManuscriptSci Transl Med. Author manuscript; available in PMC 2010 December 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript fumarate), and lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) and fatty acid oxidation (pantothenic acid). Metabolites that were highly correlated with fitness parameters were found in subjects undergoing acute exercise testing, marathon running, and in 302 subjects from a longitudinal cohort study. Exercise-induced increases in glycerol were strongly related to fitness levels in normal individuals and were attenuated in subjects with myocardial ischemia. A combination of metabolites that increased in plasma in response to exercise (glycerol, niacinamide, glucose-6-phosphate, pantothenate, and succinate) upregulated the expression of nur77, a transcriptional regulator of glucose utilization and lipid metabolism genes in skeleta...

Non-technical summary MicroRNA (miRNA) molecules are essential intracellular mediators of numerous biological processes including angiogenesis, inflammation, and mitochondrial metabolism. Recently, it has been shown that miRNAs are secreted into the bloodstream and that circulating miRNAs (c-miRNAs) may serve important endocrine functions. This study examined plasma profiles of specific c-miRNAs in healthy competitive athletes at rest and during exhaustive exercise testing, before and after a 90 day period of exercise training. In this setting, we observed four distinct patterns of c-miRNA response to exercise: (1) c-miRNAs up-regulated by acute exhaustive exercise before and after sustained exercise training, (2) c-miRNAs responsive to acute exhaustive exercise before but not after sustained exercise training, (3) c-miRNAs responsive only to sustained exercise training, and (4) non-responsive c-miRNAs. These findings set the stage for further work aimed at defining the role of c-miRNAs as fitness biomarkers and physiological mediators of exercise-induced cardiovascular adaptation.Abstract MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based 'circulating' miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 ± 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a andV O 2 max (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes inV O 2 max (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation.

Background-The clinical relevance of exercise-induced pulmonary arterial hypertension (PAH) is uncertain, and its existence has never been well studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that exercise-induced PAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal. Methods and Results-A total of 406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of exercise-induced PAH (nϭ78) was compared with resting PAH (nϭ15) and normals (nϭ16). Log-log plots of mean pulmonary artery pressure versus oxygen uptake (V O 2 ) were obtained, and a "join-point" for a least residual sum of squares for 2 straight-line segments (slopes m1, m2) was determined; m2Ͻm1ϭ"plateau," and m2Ͼm1ϭ"takeoff" pattern.