Research

Nano-Physiomics for exercise prescription

The improvement of exercise prescription for patients and athletes is the long-term goal of our scientific work (A-C). As the first research group worldwide, we reported both, a workload dependent release of cell-free circulating blood DNA (cfDNA) and a release of extracellular vesicles (EVs) during a classical cardiopulmonary exercise test (1-4).

EVs and cfDNA are macromolecular, heterogeneous molecule complexes, which are only inadequately captured by classical molecular OMICs methods - such as genomics, proteomics, metabolomics. Both nano-complexes allow conclusions about their cellular (4, 5, A), or their endogenous (I) or exogenous (II-III) origin. For this nano-molecular, organotopic, quantitative analysis, we are developing new, highly sensitive measurement methods (5, I-III).

We combine these nano-analyses with the classical monitoring of the functional behavior of the physical condition - the physiome. Progressive digitalization enables us to acquire and process increasingly large volumes of data in real time and to use telemedicine in Internet-based sports care for decentralized patient training control (6, C).

Exercise Radiomics, a newly created field of performance diagnostics, is the first application area in which we use deep learning algorithms to use skin surface temperature patterns in motion for physiomanalysis (7,D). In the future, the development of improved AI algorithms will depend very much on data quality. A long-standing research focus of the department is research on socially sensitive items, such as substance abuse and doping (8).

Literature:
1. Beiter T, Fragasso A, Hudemann J, Nieß AM, Simon, P. (2011). Short-term treadmill running as a model for studying cell-free DNA kinetics in vivo. Clinical Chemistry, 57(4), 633-636.
2. Breitbach S, Tug S, Simon P (2012). Circulating cell-free DNA: an up-coming molecular marker in exercise physiology. Sports Med 42(7):565-586.
3. Frühbeis C, Helmig S, Tug S, Simon P*, Krämer-Albers EM (2015). Physical exercise induces rapid release of small extracellular vesicles into the circulation. J Extracell Vesicles 4:28239. (*equal contribution)
4. Brahmer A, Neuberger E, Esch-Heisser L, Haller N, Jorgensen MM, Baek R, Möbius W, Simon P*, Krämer-Albers EM* (2019). Platelets, endothelial cells and leukocytes contribute to the exercise-triggered release of extracellular vesicles into the circulation. J Extracell Vesicles 8(1):1615820. (*equal contribution)
5. Ehlert T, Tug S, Brahmer A, Neef V, Heid F, Werner C, ... ,Simon, P. (2017). Establishing PNB-qPCR for quantifying minimal ctDNA concentrations during tumour resection. Scientific reports, 7(1), 1-8.
6. Pfirrmann D, Huber Y, Schattenberg JM, Simon P. (2019). Web-based exercise as an effective complementary treatment for patients with nonalcoholic fatty liver disease: intervention study. Journal of medical Internet research, 21(1), e11250.
7. Hillen B, Pfirrmann D, Nägele M, Simon P (2020). Infrared thermography in exercise physiology: The dawning of exercise radiomics. Sports Med 50(2):263-282.
8. Ulrich R, Pope HG Jr, Cléret L, Petróczi A, Nepusz T, Schaffer J, Kanayama G, Comstock RD, Simon P (2018). Doping in two elite athletics competitions assessed by randomized-response surveys. Sports Med 48(1):211-219.

Intellectual Property:
I. Simon P, Himmelreich R (2018): “Cell free DNA amplification” (F58373 DE) 102018222357.2;
II. Simon P (2007): “Detection of transgenic DNA (tDNA)“, PCT/EP2007/003385 (5402P366)
III. Simon P (2006): „Nachweis von transgener DNA (tDNA)“, Schutzrecht DE 10 2006 021 257.6 (5402P366)

Funding:
A) “Healthy Campus Mainz” Bahrmer GEK (2018-2023) Cooperative Grant: 1.518 Mio. €
B) “Blood-derived mediators of exercise induced innate and acquired stress resilience” Boehringer Ingelheim Foundation (2018-2020) Cooperative Grant: 525.100 €
C) “Decide“ Decentralized digital Environment for Consultation, data Integration, Decision making and patient Empowerment; BMBF (2021-2025) Cooperative Grant: 5.47 Mio. €
D) “INNOSPOMED - Innovative sports medical performance diagnostics, based on a novel evaluation of thermographic camera data by means of neural networks and the analytical comparison to classical parameters of sports medical performance diagnostics”, Central innovation program for SMEs (ZIM) (2020-2022) 480.000 €

Press Releases:
https://www.unimedizin-mainz.de/presse/pressemitteilungen/aktuellemitteilungen/newsdetail/article/vom-gendopingnachweis-zur-darmkrebsdiagnostik.html


After an overview, we briefly present the current research projects of the Department of Sports Medicine in the following. At the end of these descriptions you will find a list of currently published research articles.

Project overview:

Molecular exercise physiology

  • Liquid Biopsy - improvement of cfDNA quantification
  • Exercise as a model to study cell-free DNA in inflammatory signaling in health and disease
  • Exercise-triggered cellular communication via Extracellular Vesicles
  • Doping in Sports and (gene)doping detection

Web-based exercise therapy

  • HELP: Hepatic inflammation and physical performance in patients with non-alcoholic steatohepatitis
  • iPEP: Internet-based perioperative exercise program for patients with barrett's carcinoma scheduled for esophagectomy
  • ExDEP: Exercsie for depression
  • COMMED: Cystic fibrosis online mentoring program - microbiome, exercise & diet
  • SLEEP: Systemic lupus erythematosus exercise program
  • SPEER: Sports effects on emotion regulation and stress resilience

Load management of athletes

  • cfDNA for monitoring exercise load in soccer

Health promotion in living environments

  • Healthy Campus! Healthy studying at the Johannes Gutenberg University
  • “Mainz läuft!”

Infrared thermography

  •  InnoSpoMed

Abstracts of research projects

Molecular exercise physiology

Molecular exercise physiology addresses the causes of physical stress at the level of proteins, RNA and the human genetic material - DNA. The purpose is to investigate how a training stimulus affects mechanisms causing both desired effects in our body and undesirable effects, for example in the case of overtraining. Molecular exercise physiology poses the question as to which molecular or genetic conditions enable certain performances at all.

  • Exercise as a model to study cell-free DNA in inflammatory signaling in health and disease – Contact: Dr. Elmo Neuberger

Circulating cell-free DNA (cfDNA) is an important marker, which is frequently studied to assess the inflammatory state in patients with sepsis, liver disease and autoimmune disease like systemic lupus erythematosus (SLE). Physical exercise causes acute physiologic alterations including induction of inflammatory signaling processes, immune cell shifts, cytokine release, as well as an increase of cfDNA (Breitbach et al. 2012 PMID: 22694348). We established a reliable qPCR assay for the detection of cfDNA in a small amount of plasma (Breitbach et al. 2014 PMID: 24595313). Routine exercise testing implementing step-wise incremental cycling or running ergometry leads to acute elevation of cfDNA concentrations of 5.6- or 15-fold in healthy athletes (Tug et al. 2016 PMID: 27617485, Brahmer et al. 2019 PMID: 31191831, Breitbach et al. 2014 PMID: 24876361). Exercise-induced increases of cfDNA predominantly originates from cells of the haematopoietic linage (Tug et al. 2015 PMID: 25826002). In ongoing experiments we study cell type specific DNA methylation profiles to further subcharacterize proportional attribution of the cell types. To date, the knowledge on factors that trigger the cfDNA release in response to exercise and the involvement in inflammatory signaling processes is still lacking. To investigate the factors that influence the cfDNA liberation and its clinical relevance we study cfDNA and inflammatory cytokines in patients suffering from LUPUS, non-alcoholic fatty liver disease (NAFLD), or healthy untrained persons after 8 -12 weeks of exercise intervention.

  • Exercise-triggered cellular communication via Extracellular Vesicles – Contact: Dr. Alexandra Brahmer

Extracellular Vesicles (EVs) are nano-sized membrane enclosed entities which are capable of protecting and transporting a wide range of bioactive components (proteins, lipids, metabolite, nucleic acids). Diverse exercise interventions trigger the release of EVs into the circulation and they are likely involved in the health promoting physiological adaptation processes induced by regular physical exercise. In collaboration with the Institute of Developmental Biology and Neurobiology, Extracellular Vesicle Research Group (University of Mainz) we study the release kinetics, cellular origin, cargo and functions of EVs that are released into the bloodstream in response to physical exercise – ExerVs (https://cellular-neurobiology.idn.biologie.uni-mainz.de/fb-10-cellular-neurobiology/impact-of-extracellular-vesicles-released-during-exercise-exervs/).

  • Doping in Sports and (gene)doping detection – Contact: Dr. Elmo Neuberger

Doping in sports is wide spread.  An anonymized questionnaire revealed past-year doping prevalences between 43.6% and 70.1% at the World Championships in Athletics or Pan-Arab Games (Ulrich et al., 2018. PMID: 28849386). Next to conventional doping, the field of gene therapy is progressing and the innovations are becoming attractive in the sports world. Inevitable evidence underlines that biotechnological progress is likely to be exploited for doping purposes and viral vector mediated gene transfer is a conceivable scenario that might be misused, although the research in this field is still very experimental (Neuberger et al., 2012 PMID: 22508654 / Neuberger & Simon 2017 PMID: 28578328). To facilitate the detectability of gene doping we established a nested qPCR assay to detect gene doping at the highest sensitivity and specificity (Beiter et al. 2008 PMID: 19203085, Beiter et al., 2011 PMID: 20811468, Moser et al. 2012 PMID: 22539489, Moser et al. 2014 PMID: 25375130). The reproducibility of EPO gene doping detection assay was evaluated in an inter-laboratory non-human primate study (Neuberger et al. 2016 PMID: 26752352). Next to the direct detection of doping substances, indirect detection approaches like the transcriptomic approach are pursued (Neuberger et al. 2011 PMID: 22031504, Neuberger & Simon 2014 DOI: 10.5960/dzsm.2014.140). No clinical test has 100% sensitivity and 100% specificity and both values are dependent on the prevalence. This has important implications for antidoping laboratories, which could improve the validity of their test assays (Simon et al. 2018 PMID: 30300193).

Web-based exercise therapy

Contact: Dr. Daniel Pfirrmann, Dr. Alexandra Brahmer, Dr. Nils Haller, Keito Philippi, Barlo Hillen

Load management in athletes

  • Load Management– Contact: Dr. Nils Haller

Load management means the appropriate prescription, monitoring and adjustment of external and internal loads. A scientific cooperation project addresses various issues in sports science with particular focus on the development of load management approaches for athletes. Cooperation partner is the University of Salzburg and Prof. Dr. Thomas Stöggl.

Health promotion in living environments

  • Healthy Campus! Healthy studying at the Johannes Gutenberg University – Contact: Dennis Edelmann, Kristin Kalo 

The Johannes Gutenberg-University Mainz (JGU) will establish a holistic student health management. The model project „Healthy Campus Mainz – gesund studieren“, is a cooperation between the JGU University Medical Centre, the JGU and the BARMER. The BARMER is promoting the model project with 1.5 million euros within the framework of the law to strengthen health promotion and prevention (§ 20g SGB V).

The aim of the model project „Healthy Campus Mainz – gesund studieren“, is to gather scientific research on prevention and health promotion of university students in order to create evidence-based measures for maintaining and promoting health for the approximately 32.000 students of the JGU. The model project „Healthy Campus Mainz – gesund studieren“ focuses on five main topics, that are of tremendous relevance to student`s health and are considered and worked on from an interdisciplinary perspective: „movement“, „nutrition“, „communication and media use“, „medical prevention“ and „mental health“. The Department of Sport Medicine, Rehabilitation and Disease Prevention is particularly concerned with the issues surrounding physical activity and movement behaviour in the context of health. The focus is on assessing the fitness and pyhsical activity with its consequences for the musculoskeletal system and its influence on the internal organs. Based on the findings, programs to promote an active lifestyle are developed to support the integration into everyday life.

Infrared Thermography

  • InnoSpoMed 2020 – Contact: Barlo Hillen

Infrared thermography (IRT) is a non-invasive tool to measure the body surface radiation temperature (Tsr). IRT is an upcoming technology as a result of recent advancements in camera lenses, detector technique and data processing capabilities. We investigate the applicability of IRT in the context of dynamic measurements in exercise physiology and detected specific Tsr changes for different exercise types (Fig. 7&8). Close to physical exertion or during prolonged exercise IRT revealed a surface radiation pattern (Psr). We further observe how bias related to individual factors, such as skin blood flow, or related to environmental factors could be resolved by innovative technological approaches. For refined analysis, it will be necessary to develop and implement standardized and accurate pattern recognition technology capable of differentiating exercise modalities to support the evaluation of thermographic data by means of radiomics.

An extensive, national cooperation project funded by the Federal Ministry of Economics and Energy (BMWi) within the context of the "Central innovation program for SMEs (ZIM)". Innovative endurance exercise testing based on a novel evaluation of thermographic camera data by means of artificial neural networks and the analytical comparison to classical parameters of endurance exercise testing. The cooperation partners are OptoPrecision GmbH and the Institute for Computer Science of the Johannes Gutenberg-University Mainz


List of current publications
Molekulare Belastungsphysiologie

  • Brahmer, A. and Krämer-Albers, E. M. (2020). “Brainstorming”: Extracellular Vesicles in Physical Activity and Neuronal Health. Trillium Extracellular Vesicles 2020
  • Brahmer, A., Neuberger, E., Esch-Heisser, L., Haller, N., Jorgensen, M. M., Simon, P ... & Krämer-Albers, E. M. (2019). Platelets, endothelial cells and leukocytes contribute to the exercise-triggered release of extracellular vesicles into the circulation. Journal of extracellular vesicles, 8(1), 1615820.
  • Frühbeis, C., Helmig, S., Tug, S., Simon, P., & Krämer-Albers, E. M. (2015). Physical exercise induces rapid release of small extracellular vesicles into the circulation. Journal of extracellular vesicles, 4(1), 28239.
  • Helmig, S., Frühbeis, C., Krämer-Albers, E. M., Simon, P., & Tug, S. (2015). Release of bulk cell free DNA during physical exercise occurs independent of extracellular vesicles. European journal of applied physiology, 115(11), 2271-2280.

Internetbasierte Sportbetreuung

  • Boedecker SC, Philippi K, Neuberger E, Schmidt S, Pfirrmann D, Haller N, Schwarting A, Simon P, Weinmann-Menke J (2020) The effect of 12-week internet-based individualized exercise program in adults with systemic lupus erythematosus: A randomized controlled trial. JMIR Research Protocols.. https://doi.org/10.2196/preprints.18291
  • Haller N, Lorenz S, Pfirrmann D, Koch C, Lieb K, Dettweiler U, Simon P, Jung P. Individualized Web-Based Exercise for the Treatment of Depression: Randomized Controlled Trial. JMIR Ment Health 2018;5(4):e10698.
  • Hillen B, Simon P, Grimminger P.P, Gockel I, Pfirrmann D. Use of a Perioperative Web-Based Exercise Program for a Patient with Barrett’s Carcinoma Scheduled for Esophagectomy. Case Rep Oncol 2019;12:755–764.
  • Pfirrmann D, Huber Y, Schattenberg JM, Simon P Web-Based Exercise as an Effective Complementary Treatment for Patients With Nonalcoholic Fatty Liver Disease: Intervention Study. J Med Internet Res 2019;21(1):e11250.
  • Pfirrmann D, Haller N, Huber Y, Jung P, Lieb K, Gockel I, Poplawska K, Schattenberg JM, Simon P Applicability of a Web-Based, Individualized Exercise Intervention in Patients With Liver Disease, Cystic Fibrosis, Esophageal Cancer, and Psychiatric Disorders: Process Evaluation of 4 Ongoing Clinical Trials. JMIR Res Protoc 2018;7(5):e106.
  • Pfirrmann D, Tug S, Brosteanu O, Mehdorn M, Busse M, Grimminger PP, et al. Internet-based perioperative exercise program in patients with Barrett's carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial. BMC Cancer 2017 Jun 14;17(1):413.

Belastungsmanagement von Athleten

  • Haller, N., Tug, S., Breitbach, S., Jörgensen, A., & Simon, P. (2017). Increases in circulating cell-free DNA during aerobic running depend on intensity and duration. International journal of sports physiology and performance, 12(4), 455-462.
  • Haller, N., Helmig, S., Taenny, P., Petry, J., Schmidt, S., & Simon, P. (2018). Circulating, cell-free DNA as a marker for exercise load in intermittent sports. PloS one, 13(1), e0191915.
  • Haller, N., Ehlert, T., Schmidt, S., Ochmann, D., Sterzing, B., Grus, F., & Simon, P. (2019). Circulating, Cell-Free DNA for Monitoring Player Load in Professional Football. International Journal of Sports Physiology and Performance, 14(6), 718-726.
  • Haller, N., Ehlert, T., Schmidt, S., & Simon, P. Circulating DNA As A Monitoring Tool In Professional Soccer. ACSM Orlando 2019.

Gesundheitsförderung in Lebenswelten

  • Dietz, P., Reichel, J. L., Edelmann, D., Werner, A. M., Tibubos, A. N., Schäfer, M., Simon, P., Letzel, S. & Pfirrmann, D. (2020). A Systematic Umbrella Review on the Epidemiology of Modifiable Health Influencing Factors and on Health Promoting Interventions Among University Students. Front. Public Health, 8:137. doi: 10.3389/fpubh.2020.00137
  • Edelmann, D., Dietz, P., Reichel, J., Werner, A., Schäfer, M., Tibubos, A.N., Deci, N., Letzel, S., Simon, P. & Pfirrmann, D. (2020). Physische Aktivität und Sitzverhalten von Studierenden an der Johannes Gutenberg-Universität. Vortrag im Rahmen der 60. Jahrestagung der Deutschen Gesellschaft für Arbeitsmedizin und Umweltmedizin vom 2.-9. September 2020 in München.

Infrarot Thermografie

  • Hillen, B., Pfirrmann, D., Nägele, M. et al. Infrared Thermography in Exercise Physiology: The Dawning of Exercise Radiomics. Sports Med 50, 263–282 (2020). https://doi.org/10.1007/s40279-019-01210-w.
  • Hillen B, Simon P. The Temperature Surface Radiation Pattern - A non-invasive Insight into Skin Blood Flow Response to Exercise. MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, Volume: 51 Issue: 6 Pages: 491-492, JUN 2019.