NHLBI and NIDDK Workshop: Exerkines in Health, Resilience, and Diseases Executive Summary

Twenty-one experts in exerkine research from the United States, Australia, Denmark, France, Spain, Sweden, and the United Kingdom addressed four main topics in the workshop: (1) the state of current exerkine research; (2) selected known roles of exerkines in promoting health and resilience; (3) mechanisms through which exerkines exert their effects on body systems; and (4) the potential to leverage exerkines for therapeutics purposes. 

Discussions were centered on identifying knowledge and resource gaps. The workshop participants identified some current opportunities at NHLBI and NIDDK and potential ways to stimulate broad interdisciplinary collaborations to advance the field of exerkine research in health, resilience, and diseases. 

Background

Exercise is recommended by the U.S. Department of Health and Human Services as a critical component in improving health and reducing the risk of disease. Clinically, exercise has been recommended by physicians as the first line of treatment for prediabetes and obesity, and as a co-treatment plan for many chronic conditions, such as heart disease, diabetes, asthma, back pain, arthritis, depression, osteoporosis, cancer, and dementia. Exercise is also known to enhance the body’s resilience, which is described as the body’s ability of living systems to successfully maintain or return to homeostasis in response to physical, molecular, individual, social, societal, or environmental stressors or challenges. Although the health benefits of exercise are well-recognized, understanding the observed heterogeneity in individual response to exercise remains a knowledge gap. Presumably, this heterogeneity may result from the varied molecular mechanisms driving exercise-induced benefits, further investigation is needed. In response to these critical knowledge gaps, the NHLBI and NIDDK co-organized this workshop to specifically discuss the current state of knowledge and future directions with regards to the exerkine response to exercise. The themes of the workshop were to improve understanding of ways to better manage the benefits and risks of exercise; and promote therapeutic applications of exercise and exerkines in health, resilience, and diseases. The workshop was responsive to the NHLBI Strategic Vision (objectives 1–7) and NIDDK Strategic Plans. 

Summary of Discussions

Although exercise is a whole-body intervention, its effects on exerkines are highly varied, with systemic and local effects. Beginning with the discovery of lactate as the first exerkine in 1907 and describing the subsequent transformation and complexity of exerkine research to date, workshop speakers presented current findings on exerkines, including cytokines, myokines, adipokines, hepatokines, hormones, growth factors, metabolites, small RNAs, and extracellular vesicles, while acknowledging that this is “just the beginning” for further discoveries. Systemic discovery studies of exerkines have detected that thousands of molecules are significantly changed after only 10 minutes of acute exercise. Other hypothesis-driven studies detected strong associations of exerkines with specific mode and duration of exercise in both healthy and disease populations. A review of these findings clearly shows that responses to exercise are extremely heterogenous. Animal-based studies on the effects of exercise tend to translate well in human studies. Yet, because of the divergence in exercise interventions, small sample sizes, and the difficulty in performing human-based exercise interventions, the exerkine response has frequently been study-specific and challenging to compare across exercise protocols and populations. In addition, several factors that significantly affect potential outcomes also need to be controlled in future studies and reported in future publications. These factors include time of day related to circadian rhythm, fasting or fed state, diet and micronutrient intake, compliance and engagement of participants, age, sex, pre-disease conditions, and others. The NIH Common Fund large-scale human discovery project— Molecular Transducers of Physical Activity Consortium (MoTrPAC)—in conjunction with its experimental animal studies, aims to address some of these concerns and will provide a clearer view of the multi-omics landscape of exerkines to the research community.

The systemic benefits of exercise are likely due to cross tissue–organ communication induced by exercise. Conducting human studies in this area requires overcoming many remaining challenges, some of which are very specific to this field. Several in vivo and in vitro models have been developed to fill in research gaps and have provided valuable information. For instance, electric stimulation of cultured human muscle cells has been used to mimic local exercise effects. More innovative approaches in this area will greatly benefit exerkine research. 

A critical need remains in characterizing the response to exercise. Leveraging “big data” may be especially valuable. As an example, the workshop identified the need for large-scale epidemiological data of exercise response in children, adults, and older people to support therapeutic intervention of exerkines. New wearable devices have greatly enhanced the ability to continuously monitor health, resilience, and diseases. Their use in clinical exercise studies can improve compliance monitoring and enable effective capturing of individual variability within the study population, which is critically important for therapeutic evaluation. However, the cross-industry standardization needed for the use of these devices for clinical studies remains developmental, necessitating additional efforts to realize their potential. Further, the workshop participants described the need to move beyond quantitative disease phenotypes, and identified opportunities to develop new techniques to define the healthy state and characterize resilience. 

The workshop participants also explored the potential role of exerkines as therapeutics. A few reports suggest that the benefits of exercise can be transferred from one body to another through blood plasma, presumably containing many exerkines. For example, recent studies report that plasma from exercised animals can transfer several exercise-induced benefits to unexercised animals. Such findings support the concept that exerkines could be “captured” for therapeutic purposes, especially for patients who are unable to exercise (e.g., people with McArdle’s disease or who are too frail to exercise). 

Gaps, Opportunities, and Considerations

The workshop participants identified gaps and opportunities and considered ways to stimulate collaborations among exerkine researchers to advance the field.

Research Opportunities and Priorities

• More research is needed in exercise responses and exercise-induced adaptation on regeneration, immune system, metabolism, cardiovascular health, psychological health, and behavioral change at the individual and social levels.
• Deeper understanding is needed of the heterogeneity of exercise-induced phenotypic and molecular changes in the human population of all ages, training status, disease states, and genetic backgrounds.
• The proportion of ongoing efforts devoted to discovery science versus understanding of existing mechanisms of potential exerkines needs to be discussed.
• Additional investigative methods are needed to better understand inter-organ communication in humans. 

Leveraging Cutting-Edge Technology

• In addition to body mass index, physical activity and body fat composition need to be captured in electronic health records.
• Little is known about the quantitative measures of resilience in healthy and disease conditions. Innovative exploration in this area will advance our understanding of aging, health, and disease prevention.
• Approaches for remote capture and measure of exerkines and exercise responses are emerging. Further development of wearables and remote sampling technology is critical, especially for therapeutic applications.
• Standardized approaches on consistently capturing the dose exposure of exerkines (continuous or intermittent exposure) will be necessary to facilitate comparison among studies. Research is needed on the timing of sampling after exercise to capture exerkine response.
• A minimum metadata set is needed to capture proper documentation and covariate consideration in exercise studies (e.g., time of day, diet, exposure).
• A knowledge base that enables computational modeling is needed to better understand the physiological process of exercise and exerkine effects.

Considerations

• Investigate mechanisms that exerkines drive the exercise responses.
• Develop exerkines as biomarkers and predictors for health, resilience, and disease status.
• Move beyond a “muscle-centric view” regarding exercise effects and consider other factors and organs.
• Promote adherence to physical activity by supporting initiatives on (1) improving fitness, (2) engaging in higher intensity exercise (or walking), (3) doing what is enjoyable, and (4) identifying and capitalizing on the mechanisms driving the mental “award” response to exercise. 

Publication Plans

A white paper is being developed for publication.

Participating Divisions

• Division of Cardiovascular Sciences, NHLBI
• Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK

Staff Contacts

• Dr. Yunling Gao, NHLBI, gaoy2@nih.gov
• Dr. Ashley Xia, NIDDK, ashley.xia@nih.gov

Workshop Members

Co-Chairs

• Dr. Michael Snyder, Stanford University, Calif.
• Dr. Bret Goodpaster, AdventHealth Translational Research Institute, Fl.
• Dr. Lisa Chow, University of Minnesota

Members

• Dr. Mark A. Febbraio, Monash University, Australia
• Dr. Robert E. Gerszten, Harvard Medical School, Mass.
• Dr. Jacob M. Haus, University of Michigan
• Dr. Ian R. Lanza, Mayo Clinic, Rochester, Minn.
• Dr. Carl J. Lavie, Ochsner Clinical School, University of Queensland School of Medicine in New Orleans
• Dr. Chih-Hao Lee, Harvard T.H. Chan School of Public Health, Mass.
• Dr. Alejandro Lucia, European University of Madrid, Spain 
• Dr. Cedric Moro, Paul Sabatier University, Toulouse, France
• Dr. Ambarish Pandey, University of Texas Southwestern Medical Center
• Dr. Bente Klarlund Pedersen, University of Copenhagen, Denmark
• Dr. Henriette van Praag, Florida Atlantic University
• Dr. Kristin L. Stanford, Ohio State University
• Dr. Joan M. Taylor, University of North Carolina at Chapel Hill
• Dr. Alice Thackray, Loughborough University, United Kingdom
• Dr. Scott Trappe, Ball State University, Indiana
• Dr. Saul Villeda, University of California, San Francisco
• Dr. Matthew Watt, University of Melbourne, Australia
• Dr. Juleen R. Zierath, Karolinska Institute, Stockholm, Sweden

NHLBI Staff 

• Dr. Zorina Galis
• Dr. George Papanicolaou
• Dr. Selen Catania
• Dr. Jue Chen
• Dr. Kathleen Fenton
• Dr. Cashell Jaquish
• Dr. Michelle Olive
• Dr. Diane Reid
• Ms. Ilsa Rovira
• Dr. Jasmina Varagic
• Mr. Michael Wolz
• Mr. Ivan Zhorzh

NIDDK Staff

• Dr. Maren Laughlin
• Dr. Carol Renfrew Haft
• Dr. Phillip Smith