NIAMS Mechanisms of Exercise Induced Health Roundtable Summary

Monday, November 15, 2010

NIH Campus, Building 45, Room D
Bethesda, Maryland

Co-chairs
Joan McGowan, Ph.D., NIAMS
Amanda Boyce, Ph.D., NIAMS
Michael Reid, Ph.D., University of Kentucky

Introduction

The NIAMS organizes four to five roundtables on an annual basis as a part of the Institute’s long-range planning and priority-setting processes. Over the long-term, these discussions help shape the Institute’s thinking about areas of importance in our basic, translational, and clinical portfolios.

The purpose of the November 15, 2010, roundtable was to discuss opportunities and obstacles that exist in exercise research, and to understand how increased skeletal muscle activity contributes to disease prevention and increased systemic health. Prior to the meeting, participants were asked to canvas their respective communities and provide feedback that created the basis for the day’s discussion.

Increased physical activity benefits the human body in a multifactorial manner, leading to increased bone and muscle health, and reducing the burden of virtually all chronic diseases, including cardiovascular disease, obesity, type 2 diabetes, osteoporosis, sarcopenia, and depression. Conversely, the negative health and economic consequences of inactivity are undeniable. Additional research leading to a more complete understanding of the mechanisms linking increased muscle activity to disease prevention and improved health can contribute to decreased burden of common diseases. This would most likely lead to a significant increase in quality adjusted life years for many people. The mechanisms linking exercise and disease prevention may also contribute to the efficacy of physical activity as a treatment for diseases and disorders. NIAMS is one of the primary Institutes at the NIH for the study of muscle, particularly skeletal muscle. Because exercise and increased muscle activity have systemic effects, these areas are also of interest to other Institutes and Centers.

Opportunities

While scientists and the lay public both appreciate that regular exercise is beneficial to many different organs in the body, opportunities exist to determine the full impact and mechanisms of action involved. Meeting participants reviewed what is known about exercise, and noted the most important research needs and opportunities, including common data architecture, validated endpoints and outcome measures, and an understanding of the meaning of responders and non-responders as it relates to personalized medicine.

In order for the field to move into large clinical studies, a set of standard outcomes, including patient oriented outcomes, need to be agreed upon. For example, when an investigator proposes an exercise study, what does he mean by "exercise" (e.g., duration, level of intensity, frequency of participation, type of activity)? What techniques can be used to monitor and measure exercise results? How does the effect of a single acute session compare to a series of training sessions? Without agreement on such fundamental questions, data cannot be shared and analyzed across the field, thereby hindering research progress.

Basic Research

In addition to fundamental definitions for exercise, several basic scientific questions exist. Many surround the molecular mechanisms and pathways that are triggered by exercise, which are beneficial to the entire body. Muscle acts as an endocrine organ that sends signals and various factors to tissues throughout the body. Identifying and understanding the functions of these myokines, lipids, metabolic products, hormones, precursor cells, and other molecules would elucidate how exercise helps to maintain the health of many of the body’s systems. At the same time, muscle receives signals from other tissues as a result of exercise. These processes also require further investigation.

Identifying the specific molecules and factors that are involved is essential to the goal of informing therapeutic or preventive interventions. Specifically, the characterization of each of these elements could lead to targets for therapy. Other important tools and approaches that could enrich exercise investigations include genetics, epigenetics, and proteomics, as well as the study of environmental factors, like behavior and lifestyle.

While muscle, the nervous system, the immune system, and the cardiovascular system are understood to be heavily involved, more study needs to be conducted on the interactions between tissues. Clearly, this would require collaboration across fields of expertise. Interdisciplinary teams built for the purpose of studying exercise would inform multiple areas of science and medicine. For example, research into muscle regeneration following exercise would provide insight into the behavior and biology of stem cells.

Drugs designed to stimulate the pathways associated with exercise have the potential to mimic some of the benefits. However, the roundtable participants agreed that exercise affects the body in so many different ways that it would be nearly impossible to develop a single mimetic drug that could be used as a substitute for an exercise regime. They suggested that a more realistic goal would be to develop treatments that combine mimetic drugs with exercise to overcome barriers specific to a particular patient. Regardless, any pursuit of pharmacological solutions would require the ability to measure and track fitness in order to enable comparison studies.

Clinical Research

Exercise trials informed by a better understanding of fundamental mechanisms, in addition to better assessment tools and outcome measures, could lead to one of the biggest questions and challenges: how to determine the proper dose of exercise that achieves the greatest health benefit. The regimen has to be based on genetics, environment, existing conditions, and safety.

Establishing quantitative methods for evaluating exercise was a significant discussion topic throughout the day. Participants advocated for the development of common protocols with established times and frequencies, using standard techniques and tools. However, they acknowledged that the effect of patient effort is always an unknown. It was noted that it is particularly challenging to conduct exercise studies that achieve benefits for ill or frail patients, while not increasing risks to their health. Pedometers or other activity monitors were discussed as a practical, inexpensive, and informative way to quantitatively measure exercise duration, intensity, and frequency. In the end, a balance between practicality and the ability to obtain useful information needs to be found.

Measuring fitness is also important. Several tests were considered including hand grip strength, joint extension techniques, VO2 max (maximal oxygen consumption), insulin resistance, cardiovascular measures, and blood/lipid profiles. A common belief was that more fragile patients could be monitored with measurement techniques that were correlated with daily activities, such as mobility or activities needed to function independently. If the ultimate goal is to promote health so that people are not limited in their lives, this criterion can be used to monitor success. Regardless of the approach chosen, it is imperative that the measurement protocol and the analysis of data are standardized so that results can be compared across the field. This would include common milestones and endpoints that indicate fitness.

Clinical studies will rely on good animal models that would be used to establish baselines for human trials. Experiments performed with animals face many of the same challenges as those in humans. Effective, reliable, and standardized measuring tools and techniques must be available to best leverage these animal resources. Determining the level of effort is also a significant challenge when working with animals.

As discussed above, the response to various types and amounts of exercise is believed to be influenced by many factors. Clinical work must incorporate variables such as age, race, gender, lifestyle, and the disease condition of a patient. This research will hopefully be informed by basic scientific pursuits into genetic and other influences on the biochemical pathways that exercise triggers. Taken together, researchers may be able to recommend exercise regimens that are highly personalized.

Still, most attendees acknowledged that people do not exercise enough despite knowing it is good for their health. While future research will help to further inform the public of the benefits, behavioral research will be needed to determine how to best affect adoption of recommended practices. Messaging will have to target the general populace, but also health professionals who can use exercise as a disease treatment option, as well as a way to promote disease prevention. Several participants suggested that the exercise community partner with anti-obesity campaigns that share similar healthy lifestyle goals.

Obstacles

The biggest obstacle seen by participants of the roundtable was the lack of a centralized community committed to multidisciplinary exercise research. Exercise research is often made up of scientists who have expertise in different areas. Moreover, exercise affects so many aspects of biology and medicine that it is treated as a subspecialty of all areas of research rather than a field unto itself. Participants cited a need for an annual multidisciplinary exercise-specific meeting or conference. This type of meeting could catalyze and enhance recruiting and training of new researchers, as well as effectively disseminate best practices to health care providers. One important role of such a meeting would be to gain knowledge of existing clinical trials and cohort studies that might serve as a platform for ancillary studies focused on exercise.

Meeting Participants

BAMMAN, Marcas, Ph.D.
Associate Professor, Department of Physiology and Biophysics
University of Alabama at Birmingham

BOOTH, Frank, Ph.D.
Professor, Department of Biomedical Sciences
University of Missouri-Columbia

BOYCE, Amanda, Ph.D.
Director, Muscle Development and Physiology Program
Division of Musculoskeletal Diseases
NIAMS

CARTER, Robert, M.D.
Deputy Director
NIAMS

CHIN, Eva R., Ph.D.
Assistant Professor, Department of Kinesiology
University of Maryland, College Park

COOPER, Dan, M.D.
Professor, Pediatric Exercise Research Center
University of California at Irvine

GOODYEAR, Laurie, Ph.D.
Associate Professor, Joslin Diabetes Center
Harvard Medical School

HOUMARD, Joe, Ph.D.
Professor, Department of Exercise and Sport Science
East Carolina University

KATZ, Stephen I., M.D., Ph.D.
Director
NIAMS

KLIPPEL, John H., M.D.
President and CEO
Arthritis Foundation

LAUGHLIN, Maren, Ph.D.
Senior Advisor, Division of Diabetes, Endocrinology, and Metabolic Diseases
NIDDK

LIGHTFOOT, Tim, Ph.D.
Professor, Department of Health and Kinesiology
Texas A&M University

McGOWAN, Joan, Ph.D.
Director, Division of Musculoskeletal Diseases
NIAMS

MOEN, Laura, Ph.D.
Director, Division of Extramural Research Activities
NIAMS

NICKLAS, Barbara, Ph.D.
Professor, Department of Internal Medicine
Wake Forest University, WFUSM

NUCKOLLS, Glen, Ph.D.
Director, Muscle Disorders and Therapies Program
Division of Musculoskeletal Diseases
NIAMS

REID, Michael, Ph.D.
Professor, Department of Physiology
University of Kentucky

SERRATE-SZTEIN, Susana, M.D.
Director, Division of Skin and Rheumatic Diseases
NIAMS

SHEFFIELD-MOORE, Melinda, Ph.D.
Associate Professor, Department of Internal Medicine
University of Texas Medical Branch at Galveston

SLOAN, Richard, Ph.D.
Professor, Department of Psychiatry
Columbia University

STEPHENSON, Bradley, M.A., J.D.
Patient Advocate
San Antonio, TX

TRAPPE, Scott, Ph.D.
Professor, Human Performance Laboratory
Ball State University

YAN, Zhen, Ph.D.
Associate Professor, Department of Medicine
University of Virginia