Aerobic exercise and DNA methylation in postmenopausal women: An ancillary analysis of the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial

<div><p>Physical activity is associated with a lower risk of breast, colon, and endometrial cancer. Epigenetic mechanisms such as changes in DNA methylation may help to explain these protective effects. We assessed the impact of a one year aerobic exercise intervention on DNA methylation biomarkers believed to play a role in carcinogenesis. The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial was a two-armed randomized controlled trial in 320 healthy, inactive, postmenopausal women with no history of cancer. In an ancillary analysis, frozen blood samples (n = 256) were reassessed for levels of DNA methylation within LINE-1 and Alu repeats as well as within the promoter regions of <i>APC</i>, <i>BRCA1</i>, <i>RASSF1</i>, and <i>hTERT</i> genes. Differences between the exercise and control arm at 12-months, after adjusting for baseline values, were estimated within an intent-to-treat and per-protocol analysis using linear regression. No significant differences in DNA methylation between the exercise and control arms were observed. In an exploratory analysis, we found that the prospective change in estimated VO₂max was negatively associated with <i>RASSF1</i> methylation in a dose-response manner (p-trend = 0.04). A year-long aerobic exercise intervention does not affect LINE-1, Alu, <i>APC</i>, <i>BRCA1</i>, <i>RASSF1</i>, or <i>hTERT</i> methylation in healthy, inactive, postmenopausal women. Changes in DNA methylation within these genomic regions may not mediate the association between physical activity and cancer in healthy postmenopausal women. Additional research is needed to validate our findings with <i>RASSF1</i> methylation.</p><p><b>Trial Registration:</b> ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00522262" target="_blank">NCT00522262</a>.</p></div

The association between the amount of exercise, weight loss, change in VO₂ max and DNA methylation during a year-long aerobic physical activity intervention.

<p>The association between the amount of exercise, weight loss, change in VO₂ max and DNA methylation during a year-long aerobic physical activity intervention.</p

Intent-to-treat analysis comparing changes in the DNA methylation outcomes between the exercise and control groups.

<p>Intent-to-treat analysis comparing changes in the DNA methylation outcomes between the exercise and control groups.</p

CONSORT diagram of ALPHA trial ancillary study.

<p>This Consolidated Standards of Reporting Trials (CONSORT) diagram describes the inclusion and exclusion of participants included in the current trial.</p

Baseline characteristics of ALPHA trial participants included in intent-to-treat analysis.

<p>Baseline characteristics of ALPHA trial participants included in intent-to-treat analysis.</p

Per-protocol analysis comparing changes in the DNA methylation outcomes between the exercise and control groups.

<p>Per-protocol analysis comparing changes in the DNA methylation outcomes between the exercise and control groups.</p

Anthropometric measures, resting heart rate, cerebral blood flow velocity, end-tidal partial pressures for CO₂ and O₂, and blood pressures at Baseline and 6 Months.

<p>Values are mean±SD; units are mmHg except where indicated. BMI, body mass index; HR, heart rate; MCAv, maximum peak blood flow velocity in the middle cerebral artery; PET_CO2, end-tidal partial pressure for CO₂; PET_O2, end-tidal partial pressure for O₂; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; CoV, coefficient of variation; ICC, intraclass correlation coefficient.</p><p>*, p<0.05 from Baseline.</p><p>Anthropometric measures, resting heart rate, cerebral blood flow velocity, end-tidal partial pressures for CO₂ and O₂, and blood pressures at Baseline and 6 Months.</p

(A) Negative relationship between resting maximal peak cerebral blood flow velocity (MCAv) and age in men and women at Baseline. (B) Stable relationship of subjects’ cardiovascular fitness (VO_2max) values between Baseline and 6 Months.

<p>(A) Negative relationship between resting maximal peak cerebral blood flow velocity (MCAv) and age in men and women at Baseline. (B) Stable relationship of subjects’ cardiovascular fitness (VO_2max) values between Baseline and 6 Months.</p

Comparison of strategies for computing cerebrovascular responsiveness in older adults undergoing a hypercapnic challenge.

<p>Values are mean±SD. *, p<0.05 from Lower; ^†, p<0.05 from Upper; ^‡, p<0.05 from Span.</p

Relationship between resting maximal peak cerebral blood flow velocity (MCAv) and cerebrovascular response to (A) the Lower PET_CO2 step and (B) the Upper PET_CO2 step.

<p>Data presented are from Baseline testing occasion.</p