Skeletal Muscle Oxygen Delivery in Heart Failure and Breast Cancer: Mechanisms and Therapeutic Insights

Abstract

The onset of exercise requires precise cardiovascular adjustments to ensure adequate skeletal muscle oxygen delivery (Q̇O2) to meet the metabolic demands (V̇O2) of contractions. A hallmark of exercise intolerance is reduced nitric oxide (NO) bioavailability (e.g. endothelial dysfunction) and Q̇O2-to-V̇O2 mismatch that effectively reduces the partial pressure gradient for O2 diffusion across the interstitial space (PO2is) and disrupts the intracellular milieu. This presents significant quandaries for individuals diagnosed with heart failure (HF) and breast cancer (BC), both of which are malignancies associated with O2 transport dysfunction and are compounded with limited therapeutic options available to support exercise tolerance. With this, Chapter 2 examines the effects of targeting downstream of NO dysfunction (via soluble guanylyl cyclase (sGC) stimulator) to improve vascular NO-sensitivity, exercise tolerance and PO2is during contractions in HF rats. Evidence suggests that there is a bi-directional relationship between HF and BC, with each condition predisposing individuals to the other. While in HF, central O2 transport dysfunction largely precedes and promotes O2 transport limitations, BC, as an isolated condition, does not directly impact cardiac function. Therefore, in Chapter 3 we investigated the impact of tumor-bearing alone on maximal O2 uptake during exercise (V̇O2max) in BC rats. Despite no change in V̇O₂max before and after tumor growth, tumor-bearing BC rats had a reduced exercise economy, suggesting that peripheral O₂ transport limitations likely have a role in limiting sustained exercise performance. In Chapter 4, we measured the resting and contracting PO2is in BC rats and to what extent NO-signaling has in control over PO2is kinetics. We found that BC rats displayed decreased endothelium-independent vasodilation coupled with an increased reliance on basal NO production in comparison to healthy controls. Collectively, these findings highlight the critical role that NO has in regulating Q̇O₂-to-V̇O₂ matching in both HF and BC.