Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy.
OBJECTIVE
To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD).


METHODS
We performed mRNA profiling using muscles from fetopsies, infants (aged 8 to 10 months), and symptomatic patients (aged 5 to 12 years) with DMD, and age- and sex-matched controls. We performed immunohistochemistry to determine changes at the protein level and protein localization.


RESULTS
Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-kappaB pathways occurred soon after birth in DMD muscle. Two muscle wasting pathways, atrogin-1 and myostatin, were not induced at any stage of the disease. Normal muscle showed accumulation of glycolytic and oxidative metabolism capacity with increased age, but this accumulation failed in DMD. The transforming growth factor (TGF)-beta pathway was strongly induced in symptomatic patients, with expression of TGFbeta type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers.


CONCLUSIONS
Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGFbeta and failure of metabolic pathways later in the disease.
Chen
Y-W
YW
Research Center for Genetic Medicine, Children's National Medical Center, George Washington University, Washington, DC, USA. ychen@cnmcresearch.org
Nagaraju
K
K
Bakay
M
M
McIntyre
O
O
Rawat
R
R
Shi
R
R
Hoffman
E P
EP
D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000378:metabolism; D018450:Disease Progression; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D016328:NF-kappa B; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048848:MAP Kinase Kinase Kinase 5; D000077294:Receptor, Transforming Growth Factor-beta Type II