No abstract

Background: Physical activity (PA) has emerged as a promising approach to delay Alzheimer’s disease and related dementias, but the optimal intensity of PA to improve cognitive health remains unknown. Objective: To evaluate the association between duration and intensity of PA and cognitive domains (executive function, processing speed, and memory) in aging Americans. Methods: Linear regressions in hierarchical blocks for variable adjustment and the size of effect (η 2) were analyzed by using the data of 2,377 adults (age = 69.3±6.7 years) from the NHANES 2011–2014. Results: Participants with 3–6 h/week of vigorous- and >  1 h/week of moderate-intensity PA scored significantly higher in executive function and processing speed domains of cognition compared to inactive peers (η 2 = 0.005 & 0.007 respectively, p <  0.05). After adjustment, the beneficial effects of 1–3 h /week of vigorous-intensity PA became trivial for delayed recall memory domain test scores (β= 0.33; 95% CI: –0.01,0.67; η 2 = 0.002; p = 0.56). There was no linear dose-response relationship between the cognitive test scores and weekly moderate-intensity of PA. Interestingly, higher handgrip strength and higher late-life body mass index were associated with a higher performance across all cognitive domains. Conclusion: Our study supports habitual PA with superior cognition health in some but not all domains among older adults. Furthermore, increased muscle strength and higher late-life adiposity may also impact cognition.

Doxorubicin (DOX) is a highly effective chemotherapeutic used in cancer treatment. However, its use is associated with the development of cardiac dysfunction, which can negatively affect patient outcomes and reduce overall survival. While no clinical countermeasure exists to combat DOX cardiotoxicity, endurance exercise preconditioning is sufficient to preserve cardiac function following acute DOX exposure. In this regard, it is established that DOX cardiotoxicity is associated with increased mitochondrial reactive oxygen species (ROS) production and iron accumulation and that endurance exercise training stimulates an increase in the expression of the mitochondria-localized ATP-binding cassette subfamily B member 8 (ABCB8) transporter. Overexpression of ABCB8 has been shown to prevent DOX cardiac dysfunction. Therefore, we tested the hypothesis that increased levels of ABCB8 are required for exercise-induced cardioprotection against DOX toxicity. Cause and effect were determined by preventing the exercise-induced increase in ABCB8 expression using an antisense oligonucleotide (AO) designed to specifically target ABCB8. Young adult female Sprague-Dawley rats remained sedentary (SED) or were treadmill exercise trained (EX) for 2 weeks (70% VO2MAX, 1hr/day, 10 days). Immediately following each exercise bout or at identical time points, rats received either AO (10mg/kg i.p.) or saline. Rats then received either a bolus dose of DOX (20mg/kg i.p.) or saline (SAL) treatment 24 hours after the last exercise bout. Dependent measures were evaluated 48 hours after DOX or saline administration. Body weight change following DOX/SAL treatment showed significant weight loss in all DOX-treated groups, with the greatest weight change occurring in the EX-AO-DOX rats. Additionally, EX-AO-DOX treatment prevented the rescue of heart weight/tibia length seen in the EX-DOX group. Exercise capacity was assessed via a graded exercise tolerance test and revealed a significant reduction in running time in both the SED-DOX and EX-AO-DOX groups compared to SED-SAL. Interestingly, mitochondrial ROS emission was not elevated in the EX-AO-DOX treatment group compared to SED-SAL. Collectively, these results reveal that exercise-induced ABCB8 expression contributes to the protective effect of exercise against DOX cardiotoxicity. NIH R01 HL146443, NIH R01 HL144858, T32 HD043730 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Doxorubicin (DOX) is a chemotherapeutic agent highly effective at limiting cancer progression. Despite the efficacy of this anticancer drug, the clinical use of DOX is limited due to cardiotoxicity. The cardiac mitochondria are implicated as the primary target of DOX, resulting in inactivation of electron transport system complexes, oxidative stress, and iron overload. However, it is established that the cardiac mitochondrial subpopulations reveal differential responses to DOX exposure, with subsarcolemmal (SS) mitochondria demonstrating redox imbalance and the intermyofibrillar (IMF) mitochondria showing reduced respiration. In this regard, exercise training is an effective intervention to prevent DOX-induced cardiac dysfunction. Although it is clear that exercise confers mitochondrial protection, it is currently unknown if exercise training mitigates DOX cardiac mitochondrial toxicity by promoting beneficial adaptations to both the SS and IMF mitochondria. To test this, SS and IMF mitochondria were isolated from sedentary and exercise-preconditioned female Sprague Dawley rats exposed to acute DOX treatment. Our findings reveal a greater effect of exercise preconditioning on redox balance and iron handling in the SS mitochondria of DOX-treated rats compared to IMF, with rescue of cardiolipin synthase 1 expression in both subpopulations. These results demonstrate that exercise preconditioning improves mitochondrial homeostasis when combined with DOX treatment, and that the SS mitochondria display greater protection compared to the IMF mitochondria. These data provide important insights into the molecular mechanisms that are in part responsible for exercise-induced protection against DOX toxicity.

The chemotherapeutic agent doxorubicin (DOX) is highly effective at limiting cancer progression. However, systemic DOX treatment results in off‐target accumulation within cardiac mitochondria, which can cause aberrant signaling leading to dose‐dependent heart failure in cancer patients and survivors. Exercise has demonstrated preclinical and clinical efficacy in limiting the cardiotoxic effects of DOX by putatively improving mitochondrial quality and function, although this mechanism has not been fully explicated. Therefore, to further understand the molecular determinants of exercise‐mediated protection against DOX‐induced mitochondriopathy and cardiotoxicity we independently examined the cardiac subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial subpopulations. Female Sprague Dawley rats were divided (n=10/group) into 1) Sedentary‐Saline; 2) Sedentary‐DOX; 3) Exercise‐Saline; and 4) Exercise‐DOX groups. Exercise groups underwent 10 days of aerobic treadmill running (~70% VO2max, 1hr/day) with 2 days of rest after day 5. Twenty‐four hours following the last exercise bout animals received saline or DOX (20mg/kg IP) treatment. Dependent measures were evaluated 48 hours post treatment. To demonstrate that the exercise preconditioning protocol was sufficient to elicit cardiorespiratory adaptations, all groups performed an exercise tolerance test (ETT). The ETT revealed a significant increase in cardiorespiratory fitness in both exercise‐trained groups, regardless of saline or DOX treatment. In addition, evaluation of the myocardial performance index supported the premise that exercise preconditioning induces a cardioprotective phenotype against DOX toxicity. Further, analysis of the cardiac SS and IMF mitochondrial subfractions indicate that exercise preconditioning protects against DOX‐induced reactive oxygen species (ROS) emission in the SS fraction. Interestingly, IMF mitochondrial ROS emission was not affected by exercise or DOX treatment. In contrast, the IMF mitochondria respiratory control ratio (RCR) was significantly elevated in Exercise‐Saline animals compared to both sedentary groups, while no differences existed in the SS mitochondria. These findings indicate that 1) exercise preconditioning is a beneficial non‐pharmacological approach to improve cardiac outcomes following DOX treatment and that 2) cardiac mitochondrial subfractions are differentially affected by exercise and DOX treatment.