Doctor of Philosophy (PhD)
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Introduction: Exercise is well known for its many benefits on the body and most notably the heart. Recent emphasis, and significant resources, have been dedicated to elucidating the molecular mechanisms through which exercise exerts its pluripotent beneficial effects on health and the prevention of disease. A continuous evolution in this field has sought to modulate and optimize exercise in various ways to maximize the benefits. In recent years, a growing appreciation for the impact of circadian rhythms has gained traction and their influence on many essential biological functions have been integrated into exercise physiology (i.e. - chrono-exercise), as well as other important areas of research like medicine (‘chrono-pharmacology’) and nutrition (‘chrono nutrition’). Recently, several excellent studies have provided evidence in various peripheral tissues that support a robust effect of time-of-day on exercise-induced responses at the transcriptional (via RNA-sequencing), metabolic (via metabolomics), and protein levels (via proteomics). In large part, these studies have focused on the skeletal muscle, our primary mover during exercise, and have neglected the heart. The purpose of this dissertation was to address this limitation in the field and explore the impact of time-of-day on exercise-induced signaling and transcription in the heart. Methods: We investigated the effects of exercise in the hearts of 12-week-old C57/BL6 male mice (n= 42) at two time points; Zeitgeber time (ZT) 0 (beginning of light phase) and ZT12 (beginning of dark phase). Mice were habituated to treadmill exercise for 5 days at ~ZT12 (under red light) and allowed to recover for 2 days. Mice performed a single 60-minute bout of treadmill exercise beginning at ZT0 or ZT12, and were sacrificed at 3 time points; pre-exercise (SED), immediately post exercise (POST), and 1-hour post exercise (1HR). Serum was separated and tissues (hearts and quadriceps) were excised and snap frozen. Clock genes were measured via RT-PCR. Cardioprotective signaling was assessed via western blotting analysis and Enzyme Linked Immunosorbent Assay (ELISA). RNA sequencing of hearts was performed for exploration of pathway enrichment by exercise and time-of-day. Group comparisons were made using 2x3 ANOVAs. Results: The major findings of this study are a significant interaction of exercise and time-of-day on p-STAT3 in the heart. Phosphorylation of STAT3 was increased at ZT0-POST (2.74 ± 0.34), and ZT0-1HR (1.66 ± 0.09) compared to ZT0-SED (1.00 ± 0.17), as well as compared to exercised mice at ZT12 (ZT12-POST = 1.25 ± 0.13, and ZT12-1HR = 1.15 ± 0.18) (Figure 6). A significant interaction between time-of-day and exercise on autophagy was present with LC3II/I ratios increased at ZT12-POST (4.13 ± 0.32) compared to ZT0-POST (2.56 ± 0.32) (p < 0.001) (Figure 11). Transcriptional results revealed 264 DEGs at ZT0 and 216 at ZT12 with more genes being upregulated by exercise at ZT0 and the reverse (more genes down regulated by exercise) at ZT12 (186 and 108 respectively) (Figure 16 & 17). Time of day distinctly affected the transcriptional response to an acute bout of exercise in the heart. Overall, the results from this study highlight novel interactions between exercise and time-of-day, suggesting temporal coordination of exercise prescription with favorable cardiac responses that can be used to promote beneficial cardiovascular phenotypes. Conclusions: This experiment identified time as a critical mediator of exercise-induced cardiovascular signaling and transcription. Specifically, phosphorylation of STAT3 at ZT0 while Autophagy signaling at ZT12. While these data are in the context of a single bout of acute exercise, future studies will build upon these findings to test the effects of temporally specific exercise interventions in the context of cardiovascular disease including ischemia-reperfusion injury as well as cardiac rehabilitation.
acute exercise; Autophagy; Cardioprotection; Circadian rhythms; Interleukin-6
Education | Exercise Science | Medical Physiology | Physiology
University of Nevada, Las Vegas
Aguilar, Charli, "Diurnal Regulation of Exercise-Induced Myocardial Signaling and Transcription" (2022). UNLV Theses, Dissertations, Professional Papers, and Capstones. 4355.
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