Modulating the myosin super-relaxed state as a therapeutic strategy for myosin light chain-linked cardiomyopathies

In this review, we summarize a series of studies focused on cardiac myosin light chains and hereditary human mutations that cause hypertrophic (HCM), restrictive (RCM), or dilated (DCM) cardiomyopathy. In the heart, myosin serves as the molecular motor that converts the chemical energy of ATP hydrolysis into mechanical force, enabling cardiac contraction and blood pumping. Both myosin light chains, the regulatory (RLC) and essential (ELC), play critical roles in supporting and fine-tuning myosin motor function. Special emphasis is placed on the myosin super-relaxed (SRX) state, first described by Roger Cooke and colleagues more than 15 years ago. During diastole and muscle relaxation, myosin heads dynamically transition between two energetic states: the SRX state, which minimizes ATP consumption and preserves energy, and the disordered relaxed (DRX) state, in which myosin heads are more available for actin interaction but exhibit higher ATP turnover. To elucidate mechanisms underlying mutation-dependent pathological cardiac remodeling, we assessed the relative occupancy of myosin heads between the SRX and DRX states in skinned cardiac fibers from mouse models of HCM, RCM, and DCM using single-nucleotide turnover assays developed by the Cooke laboratory. Collectively, these studies demonstrate that mutation-induced alterations in myosin energetic states and dysregulation of the SRX:DRX balance constitute a central mechanism driving the distinct clinical and functional phenotypes observed in human cardiomyopathies caused by mutations in myosin RLC and ELC.