University of Vermont

Previs and Warshaw’s “Science” Study Focuses on Molecular Regulator of Heart’s Pump

Michael Previs, Ph.D., and David Warshaw, Ph.D.
Postdoctoral fellow Michael Previs, Ph.D.,and Professor and Chair of Molecular Physiology and Biophysics David Warshaw, Ph.D.

A new study published in Science by University of Vermont researchers Michael Previs, Ph.D., David Warshaw, Ph.D., and colleagues from Cincinnati Children’s Hospital provides insight into a key protein involved in regulating the tiny myosin molecular motors involved in the heart’s pumping action.

Specifically, Previs, a National Institutes of Health-supported postdoctoral fellow, and Warshaw, professor and chair of molecular physiology and biophysics, examined the molecular impact of cardiac myosin-binding protein C (cMyBP-C), a protein that regulates the myosin motors in response to stress and thus the pumping capacity of the heart. Mutations of this protein lead to hypertropic cardiomyopathy – an often hereditary condition characterized by a thickening of the heart muscle that is a well-known cause of sudden death in young athletes.

“A heart beats 70 times per minute, ejecting blood with each beat, and cMyBP-C facilitates that action,” says Previs. “However, despite its clinical importance, the role of this protein in the regulation of cardiac muscle contraction is not well understood.”

Previs, Warshaw and their research team were able to unravel some of the mystery of cMyBP-C in their study, titled “Molecular Mechanics of Cardiac Myosin-Binding Protein C in Native Thick Filaments.” Using state-of-the-art single molecule microscopy and transgenic mouse models of human heart disease, they established direct molecular evidence that cMyBP-C acts as a governor, like in a car engine, to limit the power generated by the heart’s molecular motors. The group also discovered how modifications to the structure of cMyBP-C – a condition observed in diseased hearts – have profound effects on cMyBP-C’s function.

“The molecular detail provided by studies like ours will ultimately help guide the development of therapeutic strategies to reverse the harmful effects of genetic mutations to cMyBP-C and allow individuals to live healthy lives,” Previs says.

Their work was supported scientifically by core infrastructure at UVM: the Proteomics Facility; the UVM Microscopy Imaging Center; and the UVM Instrumentation and Modeling Facility. This research was funded by the National Institutes of Health.

To learn more about the study, visit Science.