Research conducted at the University of Wyoming could help pave the way for a treatment for a neuromuscular degenerative disease that causes heart failure in humans.
Wei Guo, who was an associate professor in UW’s Department of Animal Science from 2013-19, was part of a research group that linked dysregulated ribonucleoprotein (RNP) granules — which drive neuromuscular degenerative disease — to heart failure in gene-edited pigs.
“The findings from this research may provide insights into therapeutics in human patients with RBM20 cardiomyopathy. The protein aggregation or granule formation is toxic to the cell,” Guo said. “If further studies decipher the mechanisms of dynamic formation of protein aggregation, a therapeutic strategy can be developed through interruption of granule formation.”
Cardiomyopathyis a disease of the heart muscle that makes it harder for one’s heart to pump blood to the rest of the body, and can lead to heart failure. Conservatively, 3,500 persons in the United States are affected by dilated cardiomyopathy (DCM) caused by RBM20 mutation, with many more persons affected worldwide, Guo said.
Guo is a co-author of a paper, titled “Dysregulated Ribonucleoprotein Granules Promote Cardiomyopathy in RBM20 Gene-Edited Pigs,” that was published in the Nov. 13 issue of Nature Medicine. The monthly journal publishes original peer-reviewed research in all areas of medicine on the basis of its originality, timeliness, interdisciplinary interest and impact on improving human health.
Guo, now an assistant professor of muscle biology and animal biologics at the University of Wisconsin-Madison, conducted the research during 2018. His focus was to provide materials and methods to the study, as well as experimental design and manuscript revisions. Mingming Sun, Guo’s former Ph.D. student at UW, was one of the paper’s co-authors. Sun’s contribution was to generate and provide the experimental materials in this work.
“Dr. Guo had contributed enormously to the growth of the interdisciplinary Biomedical Sciences Ph.D. Program,” said Sreejayan Nair, a UW professor of pharmacology and director of the Biomedical Sciences Ph.D. Program. “Although his home department was animal science, he mentored students, served on their graduate committees and was instrumental in developing several collaborations across disciplines, which embodies the spirit of the interdepartmental program.”
In addition to Sun, Guo also served as the major adviser for Chaoqun Zhu, who graduated from the Biomedical Sciences Ph.D. Program in 2019 and is currently pursuing a postdoctoral fellowship at the University of California-Davis.
Other contributors to the paper are from the Mayo Clinic in Rochester, Minn.; University of Texas Southwestern Medical Center in Dallas; Stanford University; Tokyo Medical and Dental University in Tokyo, Japan; European Molecular Biology Laboratory in Heidelberg, Germany; University of Verona in Verona, Italy; and the University of Texas-San Antonio.
The study focuses on RNP granules, which are a macromolecular complex formed by ribonucleic acid, or RNAs, and RNA-binding proteins, Guo says. RNP granules in the cytoplasm typically form in response to environmental stress, such as heat shock and nutrient deprivation. The formation of stress granules is designed to protect cell viability during the stress response. However, long-term granule formation is toxic to cells, according to the paper.
During the study of cardiomyopathy in pigs, some piglets displayed profound lethargy with labored, rapid, shallow breathing and frequent coughing — physical signs and symptoms of low cardiac output and pulmonary congestion.
The UW portion of the research was funded by the American Heart Association.
For Guo, the current study has origins dating back a decade.
When Guo was a postdoctoral researcher at the University of Wisconsin-Madison, he identified a new gene called RBM20. Dr. Timothy Olson, a pediatric cardiologist at the Mayo Clinic, traced DCM to a genetic mutation in RBM20.
“Deletion of this RBM20 gene in rodents results in DCM, a condition in which the heart chamber becomes enlarged, and the heart muscle becomes too weak to pump blood effectively,” Guo explains. “Mutations in this gene are present in approximately 3% of human patients. This research has uncovered a new and unexpected mechanism for heart failure.”
This landmark discovery found a correlation between the clumping of RNA-binding proteins — long linked to neurodegenerative disease — and the aggregates of protein found in the heart tissue of patients with RBM20 DCM, Guo says.