Muscle Biophysics Lab
The Molecular Basis of Fatigue and Heart Failure
Muscle generates the force and motion required to power a wide range of important tasks, from walking to the pumping of blood by the heart. The ability to accomplish these tasks is ultimately derived from the nano-scale motions of muscle’s motor enzyme, myosin. At the molecular level, myosin generates force and motion through the rotation of a long alpha helical region of myosin (a.k.a. lever-arm) while it is strongly bound to its molecular partner, actin, in a process ultimately powered by ATP hydrolysis. Advances in single molecule biophysical techniques have provided researchers with the ability to directly observe these nanometer scale motions of myosin, offering unprecedented insight into the molecular function of muscle. These advances are also helping to reveal the root molecular causes of muscle dysfunction, such as heart failure and muscular fatigue.
In the Muscle Biophysics Laboratory we use fluorescence microscopy and single molecule laser-trap techniques to gain unique insight into the molecular events that underlie basic muscle function in health and disease. In one approach, we take advantage of point mutations in contractile proteins, for example those associated with genetic cardiomyopathies, to determine the relationship between the structure and function of several muscle contractile proteins. The functional properties are quantified using the in vitro motility assay, and unitary measures of myosin’s displacement and actin binding lifetime using a “three-bead” single molecule laser-trap assay (shown above). In a related approach we determine the molecular mechanics and kinetics of myosin under conditions that simulate extreme stress such as during a heart attack or severe muscular fatigue. We hope these lines of investigation will both improve our basic understanding of muscle function and reveal the root molecular causes of related diseases, ultimately leading to improved treatments.