Breaking News
February 20, 2019 - Health Tip: Eat Less Saturated Fat
February 20, 2019 - Sleeping in contact lenses puts you at risk of dangerous infection
February 20, 2019 - “We should study that!”: How a nurse-scientist found her passion
February 20, 2019 - Cervical microbiome may influence HPV infection more than previously thought
February 20, 2019 - Sausage mislabeling in Canada is down, new study finds
February 20, 2019 - Study shows blood pressure benefits of morning exercise for older overweight/obese adults
February 20, 2019 - New screening method could catch organ rejection much earlier without a biopsy needle
February 20, 2019 - Study may have important implications for refining parenting during child’s adolescence
February 20, 2019 - Study sheds new light on how antibiotic resistance genes are transferred between bacteria
February 20, 2019 - Chronic Wasting Disease may soon spread to humans, warns CDC
February 20, 2019 - Scientists identify new genetic causes linked to abnormal pregnancies and miscarriages
February 20, 2019 - Using LyoSpeed technology to avoid residual solvent when drying HPLC fractions
February 20, 2019 - New screening tool more likely to identify sexual and labor exploitation of youth
February 20, 2019 - Newly licensed nurses work for long hours, also have a second paid job
February 20, 2019 - Physicists identify simple mechanism used by deadly bacteria to fend off antibiotics
February 20, 2019 - FDA Grants Priority Review to Genentech’s Personalized Medicine Entrectinib
February 20, 2019 - Exposure to chemicals before and after birth is associated with a decrease in lung function
February 20, 2019 - Neuroscientists reveal that simple brain region can guide complex feats of mental activity
February 20, 2019 - Study finds new link between food allergies and multiple sclerosis
February 20, 2019 - First gene therapy operation for macular degeneration is a success
February 20, 2019 - Physicians graduated outside the U.S. offer better care for Medicare patients with complex needs
February 20, 2019 - Study shows therapeutic potential of VEGF-A mRNA for regenerative angiogenesis in humans
February 20, 2019 - FDA Approves Keytruda (pembrolizumab) for the Adjuvant Treatment of Patients with Melanoma with Involvement of Lymph Node(s) Following Complete Resection
February 20, 2019 - Study identifies brain cells that modulate behavioral response to threats
February 20, 2019 - Researchers take closer look at how viruses bind cells and cause infection
February 20, 2019 - Newly developed gene therapy helps decelerate aging process
February 20, 2019 - Study suggests new treatment strategy for deadly brain cancer
February 20, 2019 - Scientists develop unique hybrid implant that imitates bone structure
February 20, 2019 - Push-ups can be tailored to meet specific needs of individuals
February 20, 2019 - Early-career job loss has long term health implications
February 20, 2019 - CVD Does Not Modify Depression-Mortality Link in Elderly
February 20, 2019 - Electrical activity early in fruit flies’ brain development could shed light on how neurons wire the brain
February 20, 2019 - Machine learning technique helps predict which asthma patients respond to corticosteroid therapy
February 20, 2019 - Self-reported sleep duration is a useful tool to measure sleep in children, study suggests
February 20, 2019 - T-cells play key role in how the body fights follicular lymphoma
February 20, 2019 - Study shows how 3D organization of genetic material helps perpetuate the species
February 20, 2019 - Researchers engineer stem cell with ‘suicide genes’ to induce cell death in all but beta cells
February 20, 2019 - Study reveals major sex differences in management of cardiovascular risk factors among U.S. adults
February 20, 2019 - Health Tip: Get Your Child to School on Time
February 20, 2019 - Shortcut strategy for screening compounds with clinical potentials for drug development
February 20, 2019 - Common acid reflux drugs tied to elevated risk for kidney disease
February 20, 2019 - Microbiome could be culprit when good drugs do harm
February 20, 2019 - Prenatal exposure to forest fires causes stunted growth in children
February 20, 2019 - Gene therapy restores hearing in mice with congenital genetic deafness
February 20, 2019 - First molecular test predicts treatment response for kidney cancer
February 20, 2019 - New method for improved visualization of single-cell RNA- sequencing data
February 20, 2019 - Researchers capture altered brain activity patterns of Parkinson’s in mice
February 20, 2019 - A possible blood test for detecting Alzheimer’s disease before symptoms show
February 20, 2019 - Primary care physicians associated with longevity, new research finds
February 19, 2019 - New study identifies many key lessons to establish sanctioned safe consumption sites
February 19, 2019 - Single CRISPR treatment can safely and stably correct genetic disease
February 19, 2019 - Multinational initiative to study familial primary distal renal tubular acidosis
February 19, 2019 - Breakthrough study highlights the promise of cell therapies for muscular dystrophy
February 19, 2019 - Subsymptom Threshold Exercise Speeds Concussion Recovery
February 19, 2019 - Midline venous catheters – infants: MedlinePlus Medical Encyclopedia
February 19, 2019 - Searching for side effects
February 19, 2019 - Humanity is all right, probably, although human extinction remains quite possible, researcher says
February 19, 2019 - Having Anesthesia Once as a Baby Does Not Cause Learning Disabilities, New Research Shows
February 19, 2019 - Anti-cancer immunotherapy could be used to fight HIV
February 19, 2019 - Customized Micropatterning for Improved Physiological Relevance
February 19, 2019 - Unique gene therapy approach paves new way to tackle rare, inherited diseases
February 19, 2019 - Activating gene that helps excite neurons reverses depression in male mice
February 19, 2019 - Science Puzzling Out Differences in Gut Bacteria Around the World
February 19, 2019 - Cells that destroy the intestine
February 19, 2019 - On recovery, vulnerability and ritual: An exhibit in white
February 19, 2019 - Scientific Duo Gets Back To Basics To Make Childbirth Safer
February 19, 2019 - COPD patients need more support when understanding new chest symptoms
February 19, 2019 - Using light-based method for production of pharmaceutical molecules
February 19, 2019 - Scientists find link between inflammation and cancer
February 19, 2019 - The High Cost Of Sex: Insurers Often Don’t Pay For Drugs To Treat Problems
February 19, 2019 - Hearing impairment associated with accelerated cognitive decline with age
February 19, 2019 - Researchers identify multiple genetic variants associated with body fat distribution
February 19, 2019 - Influenza and common cold are completely different diseases, study shows
February 19, 2019 - Scientists untangle how microbes manufacture key antibiotic compound
February 19, 2019 - Greater primary care physician supply associated with longer life spans
February 19, 2019 - HIV-1 protein suppresses immune response more broadly than thought
February 19, 2019 - Brain imaging indicates potential success of drug therapy in depressive patients
February 19, 2019 - For 2020 Dem Hopefuls, ‘Medicare-For-All’ Is A Defining Issue, However They Define It
February 19, 2019 - Specialized lung cells appear in the developing fetus much earlier than previously thought
February 19, 2019 - KU professor discusses promise of brain-computer interface to aid, restore communication
Inhibiting NF-kB improves heart function in a mouse model of Duchenne muscular dystrophy

Inhibiting NF-kB improves heart function in a mouse model of Duchenne muscular dystrophy

image_pdfDownload PDFimage_print
An image of a histological section taken from an mdx heart courtesy of Dr. Denis Guttridge of the Medical University of South Carolina. 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

Duchenne muscular dystrophy (DMD) is a devastating genetic disease that impairs cardiac and skeletal muscle development. People with DMD gradually lose ambulation in childhood, acquire respiratory and heart failure in young adulthood and succumb to 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) and improved disease management strategies have extended the life span of DMD patients and expanded the field of DMD research into later-stage outcomes such as cardiomyopathy (heart failure).

Overall, little is known about the mechanisms of DMD cardiomyopathy, particularly how individual signaling pathways contribute to its development. Breakthrough research published August 24, 2018 in Nature Communications by a large, interdisciplinary team of Medical University of South Carolina (MUSC) and Ohio State University investigators has uncovered an unexpected mechanism that underlies cardiomyopathy in DMD. The team was led by Denis Guttridge, Ph.D., professor in MUSC’s Department of Pediatrics, director of the Darby Children’s Research Institute, and associate director of Translational Sciences for the Hollings Cancer Center.

“Understanding cardiomyopathy is a significant achievement,” explains Guttridge. “About 95 percent of patients with dystrophin gene mutations (like the one that causes DMD) develop heart failure and up to 25 percent of these patients die from it. As we’ve gotten better at managing patients on ventilators and with other types of care, they’re living longer but extending life is also thought to put more stress on their hearts. So, heart failure needs to be considered in the overall management of this disease.”

The team had previously focused on the NF-κB transcription factor in skeletal muscle and, with others, showed that it regulates both physiological (differentiation, growth, and metabolism) and pathophysiological (cachexia, atrophy, and dystrophy) aspects of skeletal muscle biology. Their finding that inhibiting NF-κB improved functioning in dystrophic limb and diaphragm muscles and reduced inflammatory damage laid the foundation for investigations into NF-κB as a potential therapeutic target in DMD.

“We’d been using skeletal muscle as a platform to understand NF-κB,” explains Guttridge. “We know it drives inflammation and DMD has an inflammatory component, so then we started looking at what it does in DMD. There’s also some evidence that NF-κB plays a role in heart failure, but results differ widely based on the type of heart disease-which suggests that it may act differently in various cardiac conditions. So, we began wondering how it might contribute to cardiomyopathy in DMD.”

Using a mouse model of DMD (mdx), the team first established that NF-κB does, indeed, contribute to cardiac dysfunction in this disease. Specifically, their first set of experiments showed that cardiomyocyte NF-κB impairs cardiac response to beta-adrenergic stress. This is the first evidence to establish that cardiomyocyte-derived NF-κB signaling is instrumental in promoting dystrophic cardiac dysfunction.

Their next experiments found that cardiomyocyte NF-κB, though not required for the development of cardiac fibrosis or myocyte injury in mdx mice, still contributes to cardiac dysfunction. The question then became “How?” Published evidence indicated that genes related to calcium were enriched in the absence of NF-κB. The team followed this proposed link between NF-κB and calcium using microarray analyses to compare the hearts of NF-κB knock-out mice (mdxHRTΔIKKβ) with littermates that had intact NF-κB (mdxIKKβf/f).

They found that cardiomyocyte NF-κB ablation normalized calcium handling and significantly increased calcium gene expression.

Taking a broader look at overall gene expression patterns in dystrophic hearts lacking NF-κB, they found that it played a previously unreported functional role as a global repressor in mdx hearts.

“This mechanism was unexpected,” says Guttridge. “We thought that when the pathway was ablated, the global gene expression pattern would be down-regulated because NF-κB is supposed to be an activator. Surprisingly, we saw the opposite-about 75 percent of genes were upregulated. That told us that NF-κB was acting as a transcriptional repressor.”

The team’s next series of experiments uncovered that, although NF-κB was activated in dystrophic hearts, it was not playing its canonical role as a direct transcriptional activator but rather was modulating chromatin conformation to deplete H3K27ac. A reduction of this chromatin mark indicates that there is a repression on gene expression. This depletion, in turn, repressed the Slc8a1 gene, which codes for the NCX1 protein. And, here’s the rub— NCX1 plays a crucial role in maintaining calcium homeostasis in multiple cell types, including muscle.

“When we dug deeper to find out how and exactly what genes it was repressing, we saw that the ones that were going up were mostly calcium-handling genes like Slc8a1. Without proper mobilization of calcium, the heart doesn’t contract normally,” says Guttridge, “The reason NF-κB 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 homeostasis, the exact mechanisms driving this disruption have not previously been explored. Furthermore, these findings have important implications for the treatment of heart failure in multiple conditions including diabetes and after ischemia-reperfusion injuries. Perhaps most important, these findings highlight that targeting NF-κB could benefit both skeletal and cardiac muscle.

“I’m very excited about these findings!” says Guttridge. “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.”


Explore further:
Mitochondrial protein in cardiac muscle cells linked to heart failure, study finds

More information:
Jennifer M. Peterson et al, NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model, Nature Communications (2018). DOI: 10.1038/s41467-018-05910-1

Journal reference:
Nature Communications

Provided by:
Medical University of South Carolina

Tagged with:

About author

Related Articles