Abstract
<p>Cardiac muscle contraction results from the ATP-coupled interaction between myosin and actin/troponin (Tn)-tropomyosin (Tm) and is regulated by Ca<sup>2+</sup> ions. To supply the energy needed for pumping blood, the heart relies mainly on mitochondria metabolism to provide ATP through oxidative phosphorylation (OXPHOS). In response to different types of stimuli, the heart adapts to increased workloads through the hypertrophy of muscle cells that can be of physiological or pathological nature, e.g., hypertrophic (HCM) or restrictive (RCM) cardiomyopathy. Pathological remodeling leading to HCM and RCM can occur in response to genetic mutations in major sarcomeric genes, including <em>MYL3</em> encoding the myosin ventricular essential light chain (ELC). My Ph.D. proposal focused on the biological significance of the unique N-terminus of ELC (N-ELC), shown to make direct contacts with actin during cardiac muscle contraction. I aimed at understanding the structural, molecular, and energetic mechanisms of cardiac remodeling in transgenic ELC mouse models of pathologic vs. physiologic-like cardiac hypertrophy. Specifically, I focused on two single point mutations found in humans to be associated with HCM or RCM and a truncation mutation studied in a model of physiologic-like cardiac hypertrophy. I took advantage of transgenic mice expressing the A57G (Alanine 57-to-Glycine) mutation, as a model of HCM, and the E143K (Glutamic Acid 143-to-Lysine) mutation, as a model of RCM. A mouse model with truncated N-terminus ELC (Δ43), whose hearts hypertrophy with age but showed normal morphology and function was used as a model of near-physiological hypertrophy. I hypothesized that the N-ELC differently regulated cardiac myosin function, force production, and heart performance in ELC-pathological vs. physiological heart remodeling mice via distinct alterations in myosin cross-bridge mechanics, kinetics, and mitochondrial function. <br />
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