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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.

preterm brain scans

Early lipids in micropreemies’ diets can boost brain growth

preterm brain scans

Segmentation of a preterm brain T2-weighted MRI image at 30 gestational weeks [green=cortical grey matter; blue=white matter; grey=deep grey matter; cyan=lateral ventricle; purple=cerebellum; orange=brainstem; red=hippocampus; yellow=cerebrospinal fluid].

Dietary lipids, already an important source of energy for tiny preemies, also provide a much-needed brain boost by significantly increasing global brain volume as well as increasing volume in regions involved in motor activities and memory, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

“Compared with macronutrients like carbohydrates and proteins, lipid intake during the first month of life is associated with increased overall and regional brain volume for micro-preemies,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and senior author. “Using non-invasive magnetic resonance imaging, we see increased volume in the cerebellum by 2 weeks of age. And at four weeks of life, lipids increase total brain volume and boost regional brain volume in the cerebellum, amygdala-hippocampus and brainstem.”

The cerebellum is involved in virtually all physical movement and enables coordination and balance. The amygdala processes and stores short-term memories. The hippocampus manages emotion and mood. And the brainstem acts like a router, passing messages from the brain to the rest of the body, as well as enabling essential functions like breathing, a steady heart rate and swallowing.

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. babies is born preterm, or before 37 weeks gestation. Regions of the brain that play vital roles in complex cognitive and motor activities experience exponential growth late in pregnancy, making the developing brains of preterm infants particularly vulnerable to injury and impaired growth.

Children’s research faculty examined the impact of lipid intake in the first month of life on brain volumes for very low birth weight infants, who weighed 1,500 grams or less at birth. These micro-preemies are especially vulnerable to growth failure and neurocognitive impairment after birth.

The team enrolled 68 micro-preemies who were 32 weeks gestational age and younger when they were admitted to Children’s neonatal intensive care unit during their first week of life. They measured cumulative macronutrients – carbohydrates, proteins, lipids and calories – consumed by these newborns at 2 and 4 weeks of life. Over years, Limperopoulos’ lab has amassed a large database of babies who were born full-term; this data provides unprecedented insights into normal brain development and will help to advance understanding of brain development in high-risk preterm infants.

“Even after controlling for average weight gain and other health conditions, lipid intake was positively associated with cerebellar and brainstem volumes in very low birthweight preterm infants,” adds Katherine M. Ottolini, the study’s lead author.

According to Limperopoulos, Children’s future research will examine the optimal timing and volume of lipids to boost neurodevelopment for micro-preemies.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Early lipid intake improves brain growth in premature infants.”
    • Saturday, April 27, 2019, 1:15-2:30 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

Katie Donnelly

Firearm injuries disproportionately affect African American kids in DC Wards 7 and 8

Katie Donnelly

“Because the majority of patients in our analyses were injured through accidental shootings, this particular risk factor can help to inform policy makers about possible interventions to prevent future firearm injury, disability and death,” says Katie Donnelly, M.D.

Firearm injuries disproportionately impact African American young men living in Washington’s Wards 7 and 8 compared with other city wards, with nearly one-quarter of injuries suffered in the injured child’s home or at a friend’s home, according to a hot spot analysis presented during the Pediatric Academic Societies 2019 Annual Meeting.

“We analyzed the addresses where youths were injured by firearms over a nearly 12-year period and found that about 60 percent of these shootings occurred in Ward 7 or Ward 8, lower socioeconomic neighborhoods when compared with Washington’s six other Wards,” 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. “This granular detail will help to target resources and interventions to more effectively reduce firearm-related injury and death.”

In the retrospective, cross-sectional study, the Children’s research team looked at all children aged 18 and younger who were treated at Children’s National for firearm-related injuries from Jan. 1, 2006, to May 31, 2017. During that time, 122 children injured by firearms in Washington were treated at Children’s National, the only Level 1 pediatric trauma center in the nation’s Capitol:

  • Nearly 64 percent of these firearm-related injuries were accidental
  • The patients’ mean age was 12.9 years old
  • More than 94 percent of patients were African American and
  • Nearly 74 percent were male.

Of all injuries suffered by children, injuries due to firearms carry the highest mortality rates, the study authors write. About 3 percent of patients in Children’s study died from their firearm-related injuries. Among surviving youth:

  • Patients had a mean Injury Severity Score of 5.8. (The score for a “major trauma” is greater than 15.)
  • 54 percent required hospitalization, with a mean hospitalization of three days
  • Nearly 28 percent required surgery, with 14.8 percent transferred directly from the emergency department to the operating room and
  • Nearly 16 percent were admitted to the intensive care unit.

“Regrettably, firearm injuries remain a major public health hazard for our nation’s children and young adults,” adds Katie Donnelly, M.D., emergency medicine specialist and the study’s lead author. “Because the majority of patients in our analyses were injured through accidental shootings, this particular risk factor can help to inform policy makers about possible interventions to prevent future firearm injury, disability and death.”

Pediatric Academic Societies 2019 Annual Meeting poster presentatio

  • “Pediatric firearm-related injuries and outcomes in the District of Columbia.”
    • Monday, April 29, 2019, 5:45 p.m. to 7:30 p.m. (EST)

Katie Donnelly, M.D., emergency medicine specialist and lead author; Shilpa J. Patel, M.D., MPH, emergency medicine specialist and co-author; Gia M. Badolato, co-author; James Jackson, co-author; and Monika K. Goyal, M.D., MSCE, assistant chief of Children’s Division of Emergency Medicine and Trauma Services and senior author.

Other Children’s research related to firearms presented during PAS 2019 includes:

April 27, 8 a.m.: “Protect kids, not guns: What pediatric providers can do to improve firearm safety.” Gabriella Azzarone, Asad Bandealy, M.D.; Priti Bhansali, M.D.; Eric Fleegler; Monika K. Goyal, M.D., MSCE;  Alex Hogan; Sabah Iqbal; Kavita Parikh, M.D.; Shilpa J. Patel, M.D., MPH; Noe Romo; and Alyssa Silver.

April 29, 5:45 p.m.: “Emergency department visits for pediatric firearm-related injury: By intent of injury.” Shilpa J. Patel, M.D., MPH; Gia M. Badolato; Kavita Parikh, M.D.; Sabah Iqbal; and Monika K. Goyal, M.D., MSCE.

April 29, 5:45 p.m.: “Assessing the intentionality of pediatric firearm injuries using ICD codes.” Katie Donnelly, M.D.; Gia M. Badolato; James Chamberlain, M.D.; and Monika K. Goyal, M.D., MSCE.

April 30, 9:45 a.m.: “Defining a research agenda for the field of pediatric firearm injury prevention.” Libby Alpern; Patrick Carter; Rebecca Cunningham, Monika K. Goyal, M.D., MSCE; Fred Rivara; and Eric Sigel.

ambulance

Accident or assault? Pediatric firearm injuries differ by age

ambulance

According to a retrospective, cross-sectional study led by Children’s researchers, younger kids are more likely to be shot by accident, and odds are higher that older youths are victims of an assault involving a firearm.

An increasing number of children are injured by firearms in the U.S. each year, but the reasons these injuries happen vary. According to a new retrospective, cross-sectional study led by Children’s researchers and presented at the American Academy of Pediatrics (AAP) 2018 National Conference & Exhibition, firearm injuries vary by the intent of the person discharging the weapon. Younger kids are more likely to be shot by accident, and odds are higher that older youths are victims of an assault involving a firearm. Efforts to protect children from firearm-related injuries should factor in these differences in intent as legislation and policies are drafted, the study team suggests.

Researchers led by Shilpa J. Patel, M.D., MPH, Children’s assistant professor of pediatrics and emergency medicine, reviewed data aggregated in the Nationwide Emergency Department Sample from 2009 to 2013 looking for emergency department visits to treat firearm-related injuries suffered by children and adolescents 21 and younger. They excluded emergency department visits for firearm-related injuries attributed to air, pellet, BB or paintball guns.

Firearm-related injuries are a leading cause of injury and death for U.S. children. Some 111,839 children and youth were treated in emergency departments for firearm-related injuries, or 22,367 per year when averaged over the five-year study period. Nearly 63 percent of these youths were injured by accident; 30.4 percent were victims of assault; 1.4 percent used a firearm to injure themselves. Of note:

  • 89.3 percent were male
  • Their mean age was 18 (67.3 percent 18 to 21; 27.9 percent 13 to 17; 4.8 percent younger than 12)
  • 1 percent were discharged from the emergency department
  • 30 percent had injuries grave enough to trigger hospital admission and
  • 1 percent died from their injuries.

“Children younger than 12 were more likely to be shot by accident. By contrast, we found that the odds of experiencing firearm-related injuries due to assault were higher for youths aged 18 to 21,” Dr. Patel says. “Physicians can play a powerful role in preventing pediatric firearm-related injuries by routinely screening for firearm access and speaking with families about safe firearm storage and violence prevention,” she adds.

Some 52.1 percent of children with firearm-related injuries lived with families whose median household incomes exceeded $56,486.

American Academy of Pediatrics National Conference & Exhibition presentation

  • “Emergency department visits for pediatric firearm-related injury: by intent of injury.”

Shilpa J. Patel, M.D., MPH, assistant professor of pediatrics and emergency medicine and lead author, Gia M. Badolato, MPH, senior clinical research data manager and study co-author, Kavita Parikh, M.D., MS, associate professor of pediatrics and study co-author, and Monika K. Goyal, M.D., MSCE, assistant division chief and director of Academic Affairs and Research in the Division of Emergency Medicine and study senior author, all of Children’s National Health System; and Sabah F. Iqbal, M.D., medical director, PM Pediatrics, study co-author.