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Developmental biology - Gene Therapy

Improving DMD Heart Function In Mice

NF-kB transcription improves Duchenne muscular dystrophy (DMD) in a mouse model of the disease...


Duchenne muscular dystrophy (DMD) is a devastating genetic disease that impairs cardiac and skeletal muscle development. People with DMD gradually lose mobility in childhood, acquire respiratory and heart failure in young adulthood and die from the disease by their mid-thirties. Until recently, there has been no effective treatment for the characteristic muscle-wasting progression of this disease. Provisional FDA approval of the first DMD therapy (eteplirsen) along with improved disease management strategies have extended the life span of DMD patients, and now expanded the field of DMD research into later-stage outcomes such as cardiomyopathy (heart failure).

Little is known about the mechanisms initiating DMD cardiomyopathy, particularly which individual signaling pathways contribute to its development. However, breakthrough research published August 24, 2018 in Nature Communications by a large, interdisciplinary team of investigators from the Medical University of South Carolina (MUSC) and Ohio State University, have uncovered one unexpected mechanism.
"Understanding cardiomyopathy is a significant achievement. About 95 percent of patients with mutations to the dystrophin gene (as in DMD) develop heart failure, causing as many as 25 percent of those patients' death. Managing patients on ventilators and with other types of care has extended life for many, but also may put more stress on their hearts. So, heart failure needs to be considered in the overall management of this disease."

Denis C. Guttridge PhD, Department of Cancer Biology and Genetics, Columbus, Ohio; Center for Muscle Health and Neuromuscular Disorders, Columbus, Ohio; The Ohio State University Medical Center, Columbus, Ohio; Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.

The team had previously focused on the NF-kB transcription factor in skeletal muscle, showing that it regulates both physical and metabolic aspects of muscle biology. By inhibiting NF-kB, they improved function of dystrophic (meaning 'badly nourished') limbs and diaphragm muscles by reducing inflammation damage. This concept became the foundation for investigating NF-kB as a therapeutic target in DMD.
"We'd been using skeletal muscle as a platform to understand NF-kB. We knew it drives inflammation and DMD has an inflammatory component. So we started looking at what it does in DMD. There's some evidence NF-kB plays a role in heart failure, but results differ widely based on the type of heart disease. This suggests it may act differently in various cardiac conditions. So, we wondered how it might contribute to DMD cardiomyopathy."

Denis C. Guttridge PhD

Using a mouse model of DMD (mdx), the team established NF-kB does, indeed, contribute to cardiac dysfunction. Their first set of experiments showed how cardiomyocyte NF-kB impairs cardiac response to beta-adrenergic stress. The first evidence to ever establish cardiomyocyte-derived NF-kB signaling is instrumental in promoting dystrophic cardiac dysfunction.
Their next experiments revealed cardiomyocyte NF-kB, though not required for development of cardiac fibrosis or myocyte injury, still contributes to cardiac dysfunction. The question became "How?" Published evidence indicated genes related to calcium become enriched absent of NF-kB.

Using microarray analyses to compare the link between NF-kB and NF-kB knock-out mice hearts to those of littermates with intact NF-kB, researchers found removing NF-kB normalized calcium interaction, increasing its gene function. Taking a broad look at all gene function patterns in dystrophic hearts without NF-kB, they found it acted as a global repressor in mdx hearts.

"This mechanism was unexpected," says Guttridge. "We thought that when the pathway was ablated [removed], the global gene expression pattern would be down-regulated [suppressed] because NF-kB is supposed to be an activator. Surprisingly, we saw the opposite - about 75 percent of genes were upregulated [increased]. That told us that NF-kB was acting to repress transcription."

The team's next series of experiments uncovered that even though NF-kB was activated in dystrophic hearts, it wasn't to activate transcription, but to modify chromatin atoms and deplete H3K27ac. Reducing chromatin indicates repressed gene function. Specifically repressing the Slc8a1 gene, which codes for NCX1 protein. NCX1 plays a crucial role in maintaining calcium equilibrium in multiple cell types - including muscle cells.

"When we dug deeper to find out how and exactly what genes it was repressing, we saw mostly calcium-handling genes like Slc8a1. Without proper mobilization of calcium, the heart doesn't contract normally," adds Guttridge, "The reason NF-kB was acting as a repressor of calcium genes now made a lot of sense."

While it is understood that the pathology of dystrophic hearts is caused by disruption of calcium equilibrium, the exact mechanisms driving this disruption had not previously been explored. Furthermore, these findings have important implications for the treatment of heart failure in multiple conditions including diabetes and following ischemia-reperfusion or 'heart attack' injuries. Perhaps more importantly, these findings highlight that targeting NF-kB could benefit both skeletal and cardiac muscle.
"I'm very excited about these findings! As a scientist, you follow your hunches and try to vigorously test your hypotheses. It's so satisfying to have found a pathway that we believe contributes to the pathology of DMD, not just in skeletal muscle but also in the heart. This gives us hope that a drug can be developed that has the possibility of improving patients' lives."

Denis C. Guttridge PhD

Abstract
Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-kB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-kB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-kB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-kB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function.

Authors: Jennifer M. Peterson, David J. Wang, Vikram Shettigar, Steve R. Roof, Benjamin D. Canan, Nadine Bakkar, Jonathan Shintaku, Jin-Mo Gu, Sean C. Little, Nivedita M. Ratnam, Priya Londhe, Leina Lu, Christopher E. Gaw, Jennifer M. Petrosino, Sandya Liyanarachchi, Huating Wang, Paul M. L. Janssen, Jonathan P. Davis, Mark T. Ziolo, Sudarshana M. Sharma and Denis C. Guttridge.

The authors declare no competing financial interests.


About MUSC
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.

About the study
Dr. Olson is Professor and Chair of Molecular Biology at UT Southwestern. He holds the Pogue Distinguished Chair in Research on Cardiac Birth Defects, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Professorship in Stem Cell Research. He is also the scientific founder of Exonics Therapeutics, launched in February 2017 to advance and commercialize his research.

The study was supported, in part, by Exonics Therapeutics Inc. and grants from the National Institutes of Health, the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, and the Robert A. Welch Foundation.

Dr. Olson's team collaborated with the Royal Veterinary College. The RVC's dog colony program was supported by grants from the Wellcome Trust, Muscular Dystrophy UK, and Duchenne Ireland.

Disclosure statements: Dr. Eric Olson is a scientific co-founder of, and consultant for, Exonics Therapeutics, and has license and investment interests with the company. Dr. Leonela Amoasii is a consultant for Exonics Therapeutics and is listed as co-inventor, along with Dr. Olson, of the strategy presented in the study.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 2.4 million outpatient visits a year.


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An image of a histological section taken from an mdx heart courtesy of Dr. Denis Guttridge of the Medical University of South Carolina. Image Credit:Dr. Denis Guttridge of the Medical University of South Carolina. Modified from a supplemental figure in a Nature Communications article by Peterson et al (Nature Communications, volume 9, Article number: 3431 (2018), in accordance with the article's Creative Commons license.


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