Breaking News
December 16, 2018 - A biomarker in the brain’s circulation system may be Alzheimer’s earliest warning
December 16, 2018 - Magnesium may play important role in optimizing vitamin D levels, study shows
December 16, 2018 - The effect of probiotics on intestinal flora of premature babies
December 16, 2018 - Parents spend more time talking with kids about mechanics of using mobile devices
December 16, 2018 - Biohaven Announces Positive Results from Ongoing Rimegepant Long-Term Safety Study
December 16, 2018 - Arterial stiffness may predict dementia risk
December 16, 2018 - Study explores link between work stress and increased cancer risk
December 16, 2018 - Sex work criminalization linked to incidences of violence finds study
December 16, 2018 - Johns Hopkins researchers discover swarming behavior in fish-dwelling parasite
December 16, 2018 - Schistosomiasis prevention and treatment could help control HIV
December 16, 2018 - Early postpartum opioids linked with persistent usage
December 16, 2018 - Johns Hopkins researchers identify molecular causes of necrotizing enterocolitis in preemies
December 16, 2018 - Advanced illumination expands capabilities of light-sheet microscopy
December 16, 2018 - Alzheimer’s could possibly be spread via contaminated neurosurgery
December 16, 2018 - Unraveling the complexity of cancer biology can prompt new avenues for drug development
December 16, 2018 - Inflammatory Bowel Disease, Prostate Cancer Linked
December 16, 2018 - Cannabis youth prevention strategy should target mental wellbeing
December 15, 2018 - Recent developments and challenges in hMAT inhibitors
December 15, 2018 - Sewage bacteria found lurking in Hudson River sediments
December 15, 2018 - CDC selects UMass Amherst biostatistician model that helps predict influenza outbreaks
December 15, 2018 - Researchers reveal brain mechanism that drives itch-evoked scratching behavior
December 15, 2018 - New computer model helps predict course of the disease in prostate cancer patients
December 15, 2018 - Obesity to Blame for Almost 1 in 25 Cancers Worldwide
December 15, 2018 - How the brain tells you to scratch that itch
December 15, 2018 - New findings could help develop new immunotherapies against cancer
December 15, 2018 - World’s largest AI-powered medical research network launched by OWKIN
December 15, 2018 - Young people suffering chronic pain battle isolation and stigma as they struggle to forge their identities
December 15, 2018 - Lifespan extension at low temperatures depends on individual’s genes, study shows
December 15, 2018 - New ingestible capsule can be controlled using Bluetooth wireless technology
December 15, 2018 - Researchers uncover microRNAs involved in the control of social behavior
December 15, 2018 - Research offers hope for patients with serious bone marrow cancer
December 15, 2018 - Link between poverty and obesity is only about 30 years old, study shows
December 15, 2018 - Mass spectrometry throws light on old case of intentional heavy metal poisoning
December 15, 2018 - BeyondSpring Announces Phase 3 Study 105 of its Lead Asset Plinabulin for Chemotherapy-Induced Neutropenia Meets Primary Endpoint at Interim Analysis
December 15, 2018 - Study finds that in treating obesity, one size does not fit all
December 15, 2018 - Tenacity and flexibility help maintain psychological well-being, mobility in older people
December 15, 2018 - Study reveals role of brain mechanism in memory recall
December 15, 2018 - High levels of oxygen encourage the brain to remain in deep, restorative sleep
December 15, 2018 - Experimental HIV vaccine strategy works in non-human primates, research shows
December 15, 2018 - Genetically modified pigs could limit replication of classical swine fever virus, study shows
December 15, 2018 - FDA Approves Herzuma (trastuzumab-pkrb), a Biosimilar to Herceptin
December 15, 2018 - Cost and weight-loss potential matter most to bariatric surgery patients
December 15, 2018 - Cancer Research UK and AstraZeneca open new Functional Genomics Centre
December 15, 2018 - New research lays out potential path for treatment of Huntington’s disease
December 15, 2018 - Prestigious R&D 100 Award presented to Leica Microsystems
December 15, 2018 - Study shows septin proteins detect and kill gut pathogen, Shigella
December 15, 2018 - Study sheds new light on disease-spreading mosquitoes
December 15, 2018 - 2017 Saw Slowing in National Health Care Spending
December 15, 2018 - Monitoring movement reflects efficacy of mandibular splint
December 15, 2018 - Study supports BMI as useful tool for assessing obesity and health
December 15, 2018 - Self-guided, internet-based therapy platforms effectively reduce depression
December 15, 2018 - Organically farmed food has bigger climate impact than conventional food production
December 15, 2018 - Faster, cheaper test has potential to enhance prostate cancer evaluation
December 15, 2018 - Researchers study abnormal blood glucose levels of patients after hospital discharge
December 15, 2018 - Swedish scientists explore direct association of dementia and ischemic stroke deaths
December 15, 2018 - Study finds 117% increase in number of dementia sufferers in 26 years
December 15, 2018 - Eczema Can Drive People to Thoughts of Suicide: Study
December 15, 2018 - Link between neonatal vitamin D deficiency and schizophrenia confirmed
December 15, 2018 - Nurse denied life insurance because she carries naloxone
December 15, 2018 - Ritalin drug affects organization of pathways that build brain networks used in attention, learning
December 15, 2018 - Research pinpoints two proteins involved in creation of stem cells
December 15, 2018 - Gut bacteria may modify effectiveness of anti-diabetes drugs
December 15, 2018 - A new type of ‘painless’ adhesive for biomedical applications
December 15, 2018 - Early physical therapy associated with reduction in opioid use
December 15, 2018 - Breast cancer protection from pregnancy begins many decades later, study finds
December 15, 2018 - How often pregnant women follow food avoidance strategy to prevent allergy in offspring?
December 15, 2018 - Using machine learning to predict risk of developing life-threatening infections
December 15, 2018 - How imaginary friends could boost children’s development
December 15, 2018 - Folate deficiency creates more damaging chromosomal abnormalities than previously known
December 15, 2018 - Study provides new insights into molecular mechanisms underlying role of amyloid in Alzheimer’s disease
December 15, 2018 - For the asking, a check is in the mail to help pay for costly drugs
December 15, 2018 - UA scientists uncover biological processes leading to rare brain disorder in babies
December 15, 2018 - The largest database on industrial poisons
December 15, 2018 - ESMO Immuno-Oncology Congress showcases novel technologies set to benefit many cancer patients
December 15, 2018 - Ovid Therapeutics Announces Plans to Move into a Phase 3 Trial in Pediatric Patients Based on End-of-Phase 2 Meeting for OV101 in Angelman Syndrome
December 15, 2018 - Left ventricular noncompaction – Genetics Home Reference
December 15, 2018 - Children’s sleep not significantly affected by screen time, new study finds
December 15, 2018 - When should dementia patients stop driving? A new guidance for clinicians
December 15, 2018 - Researchers use INTEGRA’s VIAFLO 96/384 to streamline the experimental workflow
December 15, 2018 - Researchers discover protein involved in nematode stress response
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