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Inflammation and fibrosis are well-defined mechanisms involved in the pathogenesis of the incurable Laminin  α 2-deficient congenital muscular dystrophy (MDC1A), while apoptosis mechanism is barely discussed. Our previous study showed treatment with Losartan, an angiotensin II type I receptor antagonist, improved muscle strength and reduced fibrosis through transforming growth factor beta (TGF- β ) and mitogen-activated protein kinases (MAPK) signaling inhibition in the  dy   2J   /dy   2J   mouse model of MDC1A. Here we show for the first time that Losartan treatment up-regulates and shifts the nuclear factor kappa B (NF κ B) signaling pathway to favor survival  versus  apoptosis/damage in this animal model. Losartan treatment was associated with significantly increased serum tumor necrosis factor alpha (TNF- α ) level, p65 nuclei accumulation, and decreased muscle IκB- β  protein level, indicating NF κ B activation. Moreover, NF κ B anti-apoptotic target genes TNF receptor-associated factor 1 ( TRAF1 ), TNF receptor-associated factor 2 ( TRAF2 ), cellular inhibitor of apoptosis ( cIAP2 ), and Ferritin heavy chain ( FTH1 ) were increased following Losartan treatment. Losartan induced protein expression toward a pro-survival profile as BCL-2 expression levels were increased and Caspase-3 expression levels were decreased. Muscle apoptosis reduction was further confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. Thus, along with TGF- β  and MAPK signaling, NF κ B serves as an important regulatory pathway which following Losartan treatment promotes survival in the  dy   2J   /dy   2J   mouse model of MDC1A.

Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A