Mechanisms of exercise intolerance in chronic heart failure and type 2 diabetes mellitus

Chronic heart failure (CHF) and type 2 diabetes mellitus (DM) remain primary causes of mortality. Furthermore ~25-30% of CHF patients have DM, and these diabetic heart failure (D-HF) patients have an adverse prognosis. However, as yet, very few studies have examined the D-HF population in comparison to matching CHF, DM, and control patients. Therefore the current thesis described four experimental studies examining exercise intolerance and skeletal muscle abnormalities in these patient populations. The first study of this thesis employed a novel exercise test (RISE-95) to better evaluate exercise intolerance in CHF and D-HF patients. This study confirmed previous clinical findings indicating that D-HF patients have a lower peak pulmonary oxygen uptake (V̇O2peak). Furthermore this study also demonstrated that nearly half of the cohort acutely increased V̇O2peak, the mechanism of which may elucidate potential therapeutic targets. To examine potential mechanisms contributing to exercise intolerance, the second study investigated skeletal muscle mitochondrial function in chest muscle biopsies obtained from control, DM, CHF and D-HF patients. This study identified that D-HF patients exhibit both quantitative and qualitative mitochondrial impairments, with the latter residing at complex I. The next study corroborated these findings in leg biopsies from the same patients. The final study uncovered potential mechanisms possibly contributing to skeletal muscle mitochondrial impairments, including an increased mitochondrial reactive oxygen species (ROS) production and downregulated expression of key mitochondrial genes. Furthermore this study revealed that D-HF patients exhibit a type II fibre-specific atrophy and capillary rarefaction. Collectively, these studies expand our current knowledge regarding exercise intolerance in D-HF patients and how skeletal muscle impairments may contribute to the worse symptoms and outcomes seen in this growing population. The findings from this thesis are expected to guide future research endeavours, which may identify potential therapeutic targets by which exercise intolerance may be ameliorated in these patients.