Wayne State University

Wayne State University researcher discovers new molecular target for developing new treatments for cardiomyopathy and heart failure

J.P. Jin, M.D., Ph.D.

Mutations that are detrimental to the heart when occurring alone restore heart health and lower incidence of heart disease and heart failure when occurring together, a new study by a Wayne State University researcher finds.

J.P. Jin, M.D., Ph.D., professor and chair of physiology in Wayne State University’s School of Medicine, was published in the Sept. 3, 2010 issue of The Journal of Biological Chemistry. The study revealed that mutations occurring in troponin I (TnI) and troponin T (TnT), two evolutionary and functionally linked proteins in the regulatory system of the cardiac muscle, mutually cancel out each other’s negative effects and restore the heart to a normal condition. The mutations, which frequently co-occur in wild turkeys, offer a novel target for new treatments in human heart diseases such as congestive heart failure and cardiomyopathy – diseases associated with the deterioration of the function of the heart muscle.

The current work builds off a previous study, published in the Journal of Biological Chemistry in 2004, in which Jin and his students discovered that a mutation in cardiac TnI in wild turkey hearts may provide a fitness advantage by “rescuing” the effects of a heart failure mutation in cardiac TnT. In the current study, Jin’s research group duplicated the mutations using transgenic mice to examine the extent to which the two mutations influence the function of the cardiac muscle.

The study found that abnormally spliced myopathic cardiac TnT impairs systolic function, weakening the heart muscle and causing heart failure. The second mutation, a single amino acid substitution in cardiac TnI, was found to cause inadequate relaxation of the heart muscle, decreasing the diastolic function to cause heart failure.

Jin’s study also found, however, that when occurring together, the mutations mutually “rescued” the heart from the damaging effects in the transgenic mice.

TnI and TnT make up two of the three subunits of the Troponin Complex, a protein complex that plays a central role in the regulation of the contraction and relaxation of skeletal and cardiac muscle in vertebrates all the way to humans. Because humans have the same protein, the findings indicate a novel submolecular target for developing new treatments for cardiomyopathies and heart failure.

“It was very intriguing that dominantly negative mutations could mutually rescue each other and restore normal cardiac function when existing in the same heart,” Jin said. “Our future studies will delve into how this restoration occurs – findings that may greatly benefit the millions of people with heart diseases who are in danger of heart failure.”

To view the study abstract, visit http://www.jbc.org/content/285/36/27806.full.

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Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information on research at Wayne State University, visit http://www.research.wayne.edu.