By Patience Moseley, Ph.D.
FSU College of Medicine
Jose R. Pinto, Ph.D., professor in the Department of Biomedical Sciences, was awarded $2.6 million by the National Institutes of Health’s National Heart, Lung and Blood Institute to uncover the fundamental basis of cardiac muscle contraction and how changes in the genetic code alter structural components, contributing to cardiomyopathies.
Cardiomyopathies are diseases of the myocardium, or the heart muscle. Depending on the subtype of cardiomyopathy, heart muscle tissue can dilate or stiffen, reducing the heart’s ability to effectively pump blood throughout the body and eventually leading to arrhythmias, heart failure or cardiac arrest if untreated.
Current treatments are limited and may not be effective for certain mutations in the structural components that induce abnormal heart contraction.
Inherited, or familial, cardiomyopathies are largely attributed to genetic mutations encoded in sarcomeric proteins – the proteins that drive heart muscle contraction. The Pinto lab is zeroing in on one particular protein, troponin C, to reveal how mutations in two distinct regions influence the development of cardiomyopathies.
“This work is looking at the basic mechanisms of muscle and how proteins work together in the muscle to allow the heart to beat every second,” Pinto explained. Troponin C acts as a calcium sensor in the heart. When electrical impulses trigger the heart to contract, calcium flows into the muscle cell cytoplasm and binds to troponin C, evoking a change in the protein’s shape. As the protein changes structurally, it physically tugs other proteins, shifting the cardiac thin filament to expose sites where thick filament proteins attach and inducing cardiac muscle contraction.
Genetic variants, or mutations, in the troponin C gene change the protein’s structure and its ability to sense calcium flowing into the cell, eventually leading to thickening or thinning of the ventricular walls – structural hallmarks of cardiomyopathy.
The Pinto lab has developed genetic tools to investigate the in vivo function of two mutation “hotspots,” or domains, in the troponin C gene.
“We have a way to manipulate the structure of distinct domains in the troponin C gene that bind to calcium using novel genetically engineering tools. We’ve engineered the proteins in a way to block calcium binding in the so-called structural domain,” said Pinto, “This will help us understand the function of calcium binding to that specific domain, which is also a site of mutations that lead to the development of heart disease.”
With the genetic tools and improved ability to view cardiac troponin in the cardiac thin filament, the Pinto lab, backed by funding from the NIH, is well-angled to unveil the function of troponin C in health and disease.
Taking his research back to the fundamentals, Pinto — alongside his collaborators Vitold Galkin, Ph.D., associate professor at Old Dominion University, and Michelle Parvatiyar, Ph.D., associate professor at FSU Anne’s College — aims to move the needle toward tailored therapeutic interventions that improve cardiac muscle function in diseased hearts.
