Abstract
The American Diabetes Association recommends either a moderate-intensity exercise (MIE) or high-intensity exercise (HIE) regime as part of the healthy lifestyle for diabetic individuals. However, it is not known what exercise intensity is more effective at preventing or reversing the progression of diabetic heart disease (DHD). Therefore, the overarching aim of this thesis was to investigate the effectiveness of exercise at either preventing or reversing the progression of DHD.
The primary aim of this thesis was to validate the db/db mouse as a model that reasonably resembles human type-2 diabetes for the purpose of reliably assessing the impact of exercise on DHD. Hence, the diabetic (DM) and non-diabetic (ND) mice aged 8-, 16- and 24-weeks old were used. Echocardiograms revealed that 8-week old DM mice had ‘normal’ cardiac function and structure. However, DM mice developed cardiac dysfunction and adverse ventricular remodelling at 16 and 24 weeks of age.
Having validated the db/db mouse model, I next investigated the effectiveness of varying exercise intensities at preventing the onset of DHD, by subjecting the 8-week old mice with ‘normal’ cardiac function and structure to either MIE, iso-caloric HIE (ISO-HIE) or HIE for 8 weeks. The findings revealed that all exercise intensities were equally effective at preventing the onset of cardiac dysfunction and remodelling in DM mice. Given that therapeutic regulation of microRNAs (miRs) has been shown to restore the functional properties of diabetic heart, the potential role of miR in exercise-induced cardioprotection was examined. The findings revealed that cardioprotection of exercise might be partly associated with the restoration miR-126, -499 and -15b expressions, although further research is required to established a causal link between miR and cardioprotection in exercise.
Whether MIE is still cardioprotective once cardiac dysfunction is established remains controversial. Hence, I next assessed the effect of exercise in attenuating the severity of DHD. The 16-week old diabetic mice with established-cardiac dysfunction were subjected to either MIE, ISO-HIE or HIE for 8 weeks. The findings showed that ISO-HIE and HIE, but not MIE, were effective in attenuating cardiac dysfunction and remodelling in DM mice. The findings revealed that exercise-induced cardioprotection might be partly related to miR-126, -499 and -15b restorations. Intriguingly, MIE upregulated miR expressions, but it failed to normalise miR-target protein levels.
Nonetheless, it is clinically imperative to identify high-risk individuals who are asymptomatic, accordingly, allowing timely and sustained lifestyle interventions to prevent the onset of DHD. However, a reliable prognostic biomarker of DHD is lacking. Hence, the fourth aim of this thesis was to explore the role of circulating miRs as potential biomarkers of DHD. MiR analyses revealed that the circulating level of pro-angiogenic miR-126 is significantly correlated with microvascular density in the heart.
In conclusion, this thesis provides the first evidence that early MIE intervention is effective at preventing the onset of DHD; while it may become insufficient once cardiac dysfunction is well-established. It appears that exercise-induced cardioprotection is partly related to miR regulation, which provides a potential avenue to develop novel biomarkers and therapeutic agents to effectively diagnose and treat DHD, respectively.