Natural killer (NK) cells, which are found in the blood, are crucial in the prevention and treatment of cancer. They function by eliminating malignant tumors in an innate immune manner. NK cells express an array of activating and inhibitory receptors that recognize cancer cells without the need for immunization. Cytotoxicity is a process that results in damaging or destroying cells. The antitumor cytotoxicity of NK cells depends on their ability to recognize cancer cells and produce cytotoxic proteins. Mitochondrial bioenergetics is essential for optimizing NK cell effector functions, including increased cytotoxic potential and cytokine production.

Regular exercise reduces mortality associated with most cancers. An acute bout of exercise mobilizes NK cells that enter the bloodstream from peripheral tissues; it can modulate the antitumor cytotoxicity of NK cells by altering cellular protein contents in an intensity-dependent manner. However, patients with malignancies experience gradual declines in muscle strength and cardiorespiratory fitness, which can influence their ability to exercise. This may lead to a more sedentary lifestyle. High-intensity interval training (HIIT) has been shown to be a more effective modality for improving cardiorespiratory fitness than moderate-intensity continuous training in both healthy individuals and patients with cardiovascular disease.

Our study, published in the May issue of Medicine & Science in Sport & Exercise_®, involved 60 sedentary males who were randomly assigned to engage in either HIIT or moderate-intensity continuous training, or were assigned to a control group that did not receive exercise intervention. We observed that HIIT was superior to moderate-intensity training for enhancing exercise performance by increasing peak pulmonary ventilation and work-rate. Notably, both types of exercise training improved two cytotoxic characteristics of NK cells that involved the increases in cytotoxic proteins expressions and proliferative capacity of NK cells in the blood. Moreover, the two exercise regimens effectively elevated membrane potential and depressed cell matrix oxidant burden in the mitochondria of NK cells. This was associated with an increased oxygen uptake efficiency in NK cells.

NK cells are also important antiviral white blood cells that can rapidly respond to pathogens before an adaptive immune response occurs. Clinical studies in patients with COVID-19 have shown decreased NK numbers and function, resulting in decreased clearance of infected cells and increased tissue inflammation. Our previous and present studies indicate that moderate-intensity exercise training downregulated the senescent and inhibitory receptors on NK cells, thereby increasing clonal expansion and simultaneously improving NK cells’ ability to recognize and take cytotoxic action against viruses and cancer cells.

Our experimental findings could help determine effective exercise regimens for simultaneously improving cardiorespiratory fitness and the bioenergetic efficiency of NK cells in people living a sedentary lifestyle.

Jong-Shyan Wang, Ph.D., is a professor at the Graduate Institute of Rehabilitation Science at Chang Gung University, Taiwan. Dr. Wang was included in Stanford University Names World’s Top 2% of Scientists in 2021. His research focuses on developing exercise prescriptions for inflammatory/immunity, thrombotic and cardiovascular disorders.

Disclosure: This work was supported by the National Science Council of Taiwan and the Chang Gung Medical Research Program.

Viewpoints presented in SMB commentaries reflect opinions of the authors and do not necessarily represent ACSM positions or policies. Active Voice authors who have received financial or other considerations from a commercial entity associated with their topic must disclose such relationships at the time they accept an invitation to write for SMB.

• Adult weight management — counseling patients on physical activity, nutrition (in conjunction with an RD) and adherence to meal plans. 
• Bariatrics — working with patients prior to their surgery to help them understand the role that physical activity plays in weight maintenance. 
• Cardiac rehabilitation (CR) — providing traditional, facility-based CR, including Phase 3 as well as telehealth CR. 
• Cardiopulmonary stress testing — CEPs prepare patients and monitor vital signs during testing. CEPs with a master’s degree or higher supervise testing under the direction of a physician who is located in the immediate vicinity. 
• Exercise oncology — working with patients who have a cancer diagnosis and may or may not be actively receiving treatment. 
• Peripheral arterial disease (PAD) — providing supervised exercise training and risk-factor reduction education to patients with symptomatic PAD. 
• Research — supporting clinical trials where exercise is either being used as an intervention for a chronic disease or where changes in exercise capacity are an expected outcome. 

The 2018 Physical Activity Guidelines for Americans notes that there is no obvious “best amount” of physical activity and no evidence of increased risk, even among those that engage in high intensity activities. However, vigorous physical activity may acutely increase the risk of heart attack and sudden cardiac death in some individuals. Recent studies have shown that large volumes of high intensity physical activity may actually have maladaptive cardiovascular effects, including accelerated rates of cardiac scarring, atrial fibrillation and coronary artery calcium (CAC).

CAC is a highly specific subclinical marker of coronary atherosclerosis and is strongly associated with risk of future cardiovascular disease events, such as heart attack. The higher the CAC, the higher the risk. Traditionally, risk factors for the development of CAC (and heart disease) include high blood pressure, high cholesterol, diabetes and smoking, among others. However, the participants in the studies showing the link between high amounts of physical activity and CAC did not possess these traditional risk factors, leading to the controversial hypothesis that high levels of physical activity may actually increase CAC and subsequent risk of heart disease in otherwise healthy individuals.

In our study, published in the May 2022 issue of Medicine & Science in Sports & Exercise_®, we used data from the Multi-Ethnic Study of Atherosclerosis (MESA) to better understand the relationship between physical activity, CAC and cardiovascular outcomes. MESA is a large and ongoing population-based cohort study of men and women in the United States. This cohort was ideal because it has baseline information on CAC and physical activity with roughly 15 years of follow-up data. MESA includes participants from four different racial/ethnic groups (defined as “White,” “Black,” “Chinese” and “Hispanic”), making the results of our study more broadly applicable. Physical activity was assessed via a questionnaire during the baseline exam. The physical activity data was transformed into quartiles of MET-minutes (the amount of calories expended during one minute of rest) per week, with the lowest quartile serving as the reference group for the purposes of the analyses. Computed tomography scans were done to quantify CAC, and scores were dichotomized as “low CAC” (CAC < 100) and “high CAC” (CAC ≥ 100), which correspond with low and high risk, respectively. Outcomes assessed included mortality and cardiovascular disease, defined as a composite of myocardial infarction, resuscitated cardiac arrest, definite or probably angina, fatal coronary heart disease, fatal and nonfatal stroke, other atherosclerotic death, or other cardiovascular death.

We found that participants with low CAC that engaged in the highest quartile of physical activity had a reduced risk of cardiovascular disease and mortality. Participants with high CAC that engaged in the highest quartile of physical activity had a reduced risk of mortality, and no increased risk of cardiovascular disease. In fact, high levels of physical activity were not associated with an increased risk of cardiovascular disease or mortality regardless of CAC, sex or race/ethnicity. Importantly, these results were established even after controlling for traditional risk factors.

While this study suggests that high amounts of physical activity appear to be safe, even among those at high risk, it was conducted in an observational cohort. Future studies should be done to confirm these data. Additionally, we were unable to account for differences in physical activity levels over time. However, our results should empower patients to be physically active and encourage health care providers to promote physical activity and exercise, even among those at high risk of cardiovascular disease. 

Charles A. German, M.D., M.S., is an assistant professor and preventive cardiologist at the University of Chicago. He is the current director of cardiac rehabilitation and serves on the editorial board of the Journal of Cardiopulmonary Rehabilitation and Prevention. He also serves on the physical activity committee and obesity committee for the American Heart Association. His research interests focus on accelerometry-based physical activity; relationships between physical activity, sleep, and sedentary behavior; and the safety of physical activity in high risk populations. He can be reached at cagerman@uchicago.edu or on Twitter @DrGermanMD.

Viewpoints presented in SMB commentaries reflect opinions of the authors and do not necessarily represent ACSM positions or policies. Active Voice authors who have received financial or other considerations from a commercial entity associated with their topic must disclose such relationships at the time they accept an invitation to write for SMB.