Myosin is the molecular motor in muscle that, in association with its binding partner actin, consumes fuel in the form of ATP to power contraction. It provides the impulsive force to move actin against a resisting force and do work. Myosin in association with actin powers movement in skeletal, cardiac, and smooth muscle tissues and motility in non-muscle cells.
Several inheritable skeletal muscle diseases cause muscle weakness. Inheritable cardiac diseases present variable maladies thought to be roughly correlated to either gain or loss in myosin function. Gene sequencing has associated several myosin motor mutations with skeletal, heart and smooth muscle diseases, leading to hypotheses relating myosin function anomalies with specific maladies that are investigated in the laboratory of Thomas P. Burghardt, Ph.D.
- Mutation deviates the myosin lever-arm swing trajectory as it develops force in the heart. In papillary muscle fibers, this effect is detected by single molecule orientation super-resolution. Project involves muscle physiology, single molecule total internal reflection fluorescence (TIRF) microscopy and pattern recognition software.
- Individual variability in myosin motility and drug-protein interaction kinetics are detectable from biopsy specimens in constant flow microfluidic and nanofluidic devices. Project involves design, simulation (FEM), fabrication, operation of microfluidic and nanofluidic devices, and continuous flow kinetics.
- Aorta myosin mutation has a role in aneurysm disease.
- Single molecule motility measuring myosin step size using Qdot-labeled actin and myosin lever-arm orientation super-resolution correlates actin displacement with myosin lever-arm rotary movement and provides deeper insight into contractility characteristics modified by disease. Focus is on identifying functional impairment in skeletal and heart disease-implicated mutants of human skeletal and cardiac myosin.
- Myosin surface loops provide control structures for nanomotor engineering. Project involves rational protein design, muscle protein biochemistry, enzyme assay, microscope-based motility measurements and molecular dynamics simulation.
Significance to patient care
Disease-implicated myosin mutation suggests a genetic origin for illness, although the pathway linking the diminished myosin function and muscle weakness or heart failure has proven to be neither simple nor direct.
Nonetheless, a genetic origin to clinically diagnosed heart disease appears to select the most severely ill, indicating a practical reason to identify the protein function affected by the mutant. Furthermore, characterizing myosin functionality and its alteration by disease-implicated mutation is the only rational means to elucidate the molecular basis for disease and identify the targets for smarter therapy.