Cellular mechanisms and novel treatments of skeletal muscle weakness in heart failure with preserved ejection fraction

Heart failure (HF) is no longer considered a simple syndrome of cardiac dysfunction but includes several skeletal muscle alterations that limit functional capacity and quality of life. However, compared to HF with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by HF with preserved ejection fraction (HFpEF) remain poorly explored with limited treatments. This thesis, therefore, aimed to reveal new insights into the cellular mechanisms underlying skeletal muscle pathology in HFpEF by examining the effects of pharmacological, physical-loading (exercise), and nutritional interventions. Using a well-established obese rat model, this thesis provides new evidence that: HFpEF induces multiple skeletal muscle alterations, including contractile dysfunction, fibre atrophy, capillary loss and an impaired exercise hyperaemia; pharmacological treatments improved cardiac function in HFpEF but did not impact skeletal muscle remodelling; overload-induced skeletal muscle hypertrophy is impaired in HFpEF and linked to mitochondrial but not vascular impairments; and acute caloric restriction treatment in HFpEF partially restored the hypertrophic response that was related to improved myonuclear accretion. Collectively, these findings extend current knowledge of muscle pathophysiology in HFpEF and may facilitate future therapeutic approaches.