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sketch of muscle cells

Losing muscle to fat: misdirected fate of a multipotent stem cell drives LGMD2B

Fibro/adipogenic precursors (FAPs) control the onset and severity of disease in limb-girdle muscular dystrophy type 2 (LGMD2B)

Fibro/adipogenic precursors (FAPs) control the onset and severity of disease in limb-girdle muscular dystrophy type 2 (LGMD2B). a) Healthy and/or pre-symptomatic LGMD2B muscle contains resident FAPs. b) After myofiber injury, inflammatory cells invade and trigger FAP proliferation. c) In symptomatic LGMD2B muscle, there is a gradual accumulation of extracellular AnxA2, which prolongs the pro-inflammatory environment, causing excessive FAP proliferation. d) Blocking aberrant signaling due to AnxA2 buildup blocks FAP accumulation and thus preventing adipogenic loss of dysferlinopathic muscle. Credit: “Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B.” Published online June 3, 2019, in Nature Communications. Marshall W. Hogarth, Aurelia Defour, Christopher Lazarski, Eduard Gallardo, Jordi Diaz Manera, Terence A. Partridge, Kanneboyina Nagaraju and Jyoti K. Jaiswal. https://rdcu.be/bFu9U.

Research led by faculty at Children’s National published online June 3, 2019, in Nature Communications shows that the sudden appearance of symptoms in limb-girdle muscular dystrophy type 2 (LGMD2B) is a result of impaired communication between different cell types that facilitate repair in healthy muscle. Of particular interest are the fibro/adipogenic precursors (FAPs), cells that typically play a helpful role in regenerating muscle after injury by removing debris and enhancing the fusion of muscle cells into new myofibers.

LGMD2B is caused by mutations in the DYSF gene that impair the function of dysferlin, a protein essential for repairing injured muscle fibers. Symptoms, like difficulty climbing or running, do not appear in patients until young adulthood. This late onset has long puzzled researchers, as the cellular consequences of dysferlin’s absence are present from birth and continue through development, but do not impact patients until later in life.

The study found that in the absence of dysferlin, muscle gradually increases the expression of the protein Annexin A2 which, like dysferlin, facilitates repair of injured muscle fiber. However, increasing Annexin A2 accumulates outside the muscle fiber and drives an increase in FAPs within the muscle as well as encourages these FAPs to differentiate into adipocytes, forming fatty deposits. Shutting down Annexin A2 or blocking the adipocyte fate of FAPs using an off-the-shelf medicine arrests the fatty replacement of dysferlinopathic muscle.

“We propose a feed-forward loop in which repeated myofiber injury triggers chronic inflammation which, over time, creates an environment that promotes FAPs to accumulate and differentiate into fat. This, in turn, contributes to more myofiber damage,” says Jyoti K. Jaiswal, MSc, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National and the study’s senior author.

“Adipogenic accumulation becomes the nucleating event that results in an abrupt decline in muscle function in patients. This new view of LGMD2B disease opens previously unrealized avenues to intervene,” adds Marshall Hogarth, Ph.D., the study’s lead author.

Joyti Jaiswal

“We propose a feed-forward loop in which repeated myofiber injury triggers chronic inflammation which, over time, creates an environment that promotes FAPs to accumulate and differentiate into fat. This, in turn, contributes to more myofiber damage,” says Jyoti K. Jaiswal, MSc, Ph.D.

A research team led by Jaiswal collaborated with Eduard Gallardo and Jordi Diaz Manera, of Hospital de la Santa Creu in Barcelona, Spain, to examine muscle biopsies from people with LGMD2B who had mild to severe symptoms. They found that adipogenic deposits originate in the extracellular matrix space between muscle fibers, with the degree of accumulation tied to disease severity. They found a similar progressive increase in lipid accumulation between myofibers predicted disease severity in dysferlin-deficient experimental models. What’s more, this process can be accelerated by muscle injury, triggering increased adipogenic replacement in areas that otherwise would be occupied by muscle cells.

“Accumulation and adipogenic differentiation of FAPs is responsible for the decline in function for dysferlinopathic muscle. Reversing this could provide a therapy for LGMD2B, a devastating disease with no effective treatment,” predicts Jaiswal as the team continues research in this field.

Promising off-the-shelf drugs include batimastat, an anti-cancer drug that inhibits the extracellular matrix enzyme matrix metalloproteinase. This drug reduces FAP adipogenesis in vitro and lessens injury-triggered lipid formation in vivo. In experimental models, batimastat also increases muscle function.

In addition to Jaiswal, Hogarth, Gallardo and Diaz Manera, other study co-authors include Aurelia Defour, Christopher Lazarski, Terence A. Partridge and Kanneboyina Nagaraju, all of Children’s National.

Financial support for research described in this post was provided by the Muscular Dystrophy Association under awards MDA477331 and MDA277389, the National Institute of Arthritis and Musculoskeletal and Skin Diseases under award R01AR055686 and the National Institutes of Health under awards K26OD011171, R24HD050846 and P50AR060836.

Fewer than 60% of young women diagnosed with STIs in emergency departments fill scripts

Fewer than 60% of young women diagnosed with sexually transmitted infections (STIs) in the emergency department fill prescriptions for antimicrobial therapy to treat these conditions, according to a research letter published online May 28, 2019, by JAMA Pediatrics.

Adolescents make up nearly half of the people diagnosed with sexually transmitted infections each year. According to the Centers for Disease Control and Prevention, untreated sexually transmitted diseases in women can cause pelvic inflammatory disease (PID), an infection of the reproductive organs that can complicate getting pregnant in the future.

“We were astonished to find that teenagers’ rates of filling STI prescriptions were so low,” says Monika K. Goyal, M.D., MSCE, assistant chief of Children’s Division of Emergency Medicine and Trauma Services and the study’s senior author. “Our findings demonstrate the imperative need to identify innovative methods to improve treatment adherence for this high-risk population.”

The retrospective cohort study, conducted at two emergency departments affiliated with a large, urban, tertiary care children’s hospital, enrolled adolescents aged 13 to 19 who were prescribed antimicrobial treatment from Jan. 1, 2016, to Dec. 31, 2017, after being diagnosed with PID or testing positive for chlamydia.

Of 696 emergency department visits for diagnosed STIs, 208 teenagers received outpatient prescriptions for antimicrobial treatments. Only 54.1% of those prescriptions were filled.

“Teenagers may face a number of hurdles when it comes to STI treatment, including out-of-pocket cost, access to transportation and confidentiality concerns,” Dr. Goyal adds.

Future studies will attempt to identify barriers to filling prescriptions in order to inform development of targeted interventions based in the emergency department that promote adherence to STI treatment.

In addition to Dr. Goyal, study co-authors include Lead Author, Alexandra Lieberman, BA, The George Washington University School of Medicine & Health Sciences; and co-authors Gia M. Badolato, MPH, and Jennifer Tran, PA-C, MPH, both of Children’s National.

Ololade Okito

Parents of older, healthier newborns with less social support less resilient

Ololade Okito

“We know that having a child hospitalized in the NICU can be a high-stress time for families,” says Ololade Okito, M.D., lead author of the cross-sectional study. “The good news is that as parental resiliency scores rise, we see a correlation with fewer symptoms of depression and anxiety.

Parents of older, healthier newborns who had less social support were less resilient during their child’s hospitalization in the neonatal intensive care unit (NICU), a finding that correlates with more symptoms of depression and anxiety, according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Resiliency is the natural born, yet adaptable ability of people to bounce back in the face of significant adversity. Published research indicates that higher resilience is associated with reduced psychological distress, but the phenomenon had not been studied extensively in parents of children hospitalized in a NICU.

“We know that having a child hospitalized in the NICU can be a high-stress time for families,” says Ololade Okito, M.D., lead author of the cross-sectional study. “The good news is that as parental resiliency scores rise, we see a correlation with fewer symptoms of depression and anxiety. Parents who feel they have good family support also have higher resilience scores.”

The project is an offshoot of a larger study examining the impact of peer mentoring by other NICU parents who have experienced the same emotional rollercoaster ride as their tiny infants sometimes thrived and other times struggled.

The research team enrolled 35 parents whose newborns were 34 weeks gestation and younger and administered a battery of validated surveys, including:

Forty percent of these parents had high resilience scores; parents whose infants were a mean of 27.3 gestational weeks and who had more severe health challenges reported higher resilience. Another 40% of these parents had elevated depressive symptoms, while 31% screened positive for anxiety. Parental distress impairs the quality of parent-child interactions and long-term child development, the research team writes.

“Higher NICU-related stress correlates with greater symptoms of depression and anxiety in parents,” says Lamia Soghier, M.D., MEd, medical director of Children’s neonatal intensive care unit and the study’s senior author. “Specifically targeting interventions to these parents may help to improve their resilience, decrease the stress of parenting a child in the NICU and give these kids a healthier start to life.”

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Parental resilience and psychological distress in the neonatal intensive care unit (PARENT) study”
    • Tuesday, April 30, 2019, 7:30 a.m. (EST)

Ololade Okito, M.D., lead author; Yvonne Yui, M.D., co-author; Nicole Herrera, MPH, co-author; Randi Streisand, Ph.D., chief, Division of Psychology and Behavioral Health, and co-author; Carrie Tully, Ph.D., clinical psychologist and co-author; Karen Fratantoni, M.D., MPH, medical director, Complex Care Program, and co-author; and Lamia Soghier, M.D., MEd, medical unit director, neonatal intensive care unit, and senior author; all of Children’s National.