PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the US and globally. Physical activity has been clearly shown to improve CVD risk factors and reduce disease incidence; thus, the US (and other countries) have guidelines for physical activity. Current guidelines call for both aerobic exercise (AE; e.g., walking) and resistance exercise (RE; e.g., weight lifting). Research on AE, including its dose-response, and health has been extensive; consequently, guidelines are clear on what should be done (≥150 min/week of moderate intensity AE). In contrast, there is only limited research on RE; thus, guidelines lack clarity (2 times/week, but with unspecified duration). A recent meta-analysis of observational studies reported a J-shaped relation where more time in RE was associated with lower CVD risk only up to 60 min/week, beyond which CVD risk reduction attenuated, and indeed appeared to increase at ≥130 min/week. While it remains unclear, postulated mechanisms that may underlie the higher CVD risk with higher RE doses include increased arterial stiffness due to increased sympathetic activity during RE and chronic inflammation occurring with higher RE doses, leading to atherosclerosis and systemic vascular damage. There are currently no randomized controlled trials that have directly tested and compared multiple doses of RE on CVD risk factors in general population. Thus, to provide data that are crucial for exercise prescription and translation to public health practice, this proposal seeks to conduct a randomized controlled trial among 240 adults with overweight or obesity (since adiposity increases CVD risk). In the first 6 months (Phase 1), they will participate in a supervised, lab-based RE training phase. Participants will be randomly assigned to 4 doses of RE (n=60 per group): 0 min/session (control), 15 min/session, 30 min/session, or 60 min/session, all for 2 sessions/week per current RE guidelines. All 4 groups also will be asked to do AE for 30 min/session, 2 sessions/week, congruent with the current guidelines that require both RE and AE. A primary aim will be to assess changes from baseline to 6 months in a composite CVD risk score using 4 well-established CVD risk factors: systolic blood pressure, low-density lipoprotein cholesterol, fasting glucose, and percent body fat. There will be sufficient statistical power to detect changes in the risk score, based on prior data. Another primary aim will be to examine potential mechanisms underlying the J-shaped relation of RE on CVD risk, by assessing changes from baseline to 6 months in aortic arterial stiffness (purse wave velocity) and inflammatory markers (e.g., CRP, IL-6, TNF-α). In the second 6 months (Phase 2), there will be an unsupervised, self- maintenance phase where all will be provided with free health club memberships and asked to continue with their assigned intervention in Phase 1. Continued adherence to their assigned RE dose will be assessed to address the secondary aim of: which dose(s) will engender best participation in a free-living situation? This trial will fill important gaps in knowledge on effective, safe, and practical dose(s) of RE for CVD prevention.

PROJECT NARRATIVE Physical activity reduces the risk of cardiovascular disease (CVD), the leading cause of death in the US and globally. However, while we know a great deal about how much aerobic exercise (e.g., walking, jogging) to prescribe in order to reduce CVD risk, we know far less about how much resistance exercise (e.g., weight lifting) to prescribe. This proposed project will add important knowledge by (i) testing the effects of different doses of resistance exercise on CVD risk factors in a clinical trial among adults with overweight or obesity, (ii) exploring possible biologic mechanisms linking resistance exercise to CVD risk, and (iii) identifying which dose(s) of resistance exercise is (are) associated with best compliance, after trial intervention, in a free-living environment.