P.8.10 Losartan up-regulates NF κ B signaling pathway and favors survival versus apoptosis in the dy2J/dy2J mouse model of Congenital Muscular Dystrophy

• Published in: Neuromuscular disorders : NMD 2013-10, Vol.23 (9), p.782-782
• Main Authors: Elbaz, M, Yanay, N, Gelb, S, Rabie, M, Rosenbaum, S. Mitrani, Nevo, Y
• Format: Article
• Language: English
• Subjects: Neurology
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2013.06.511

Congenital Muscular Dystrophy (CMD) is a group of genetic disorders characterized by progressive loss of muscle strength and integrity. Merosin deficient congenital muscular dystrophy type 1A (MDC1A) is a common form of this disorder. Children affected with MDC1A suffer from early onset severe hypotonia and weakness with significant motor milestone delay. Often they do not achieve independent ambulation and die in the second or third decade. Despite extensive advances in diagnosis, cellular and molecular understanding, MDC1A remains a disease without a cure or any proven therapeutic option to relieve or slow disease progression. Our experimental data suggest that treatment with Losartan, an Angiotensin II type I receptor antagonist, results in significant clinical improvements and amelioration of fibrosis in the dy2J/dy2J mouse model of CMD through inhibition of TGF β and MAPK signaling. We further examined Losartan’s effect on the cellular network, focusing on NF κ B signaling. Previous studies suggested a role of NF κ B in promoting muscle inflammation, necrosis and degeneration in Duchenne muscular dystrophy patients and animal models. Contrary to this, here we show that Losartan’s beneficial effect in the dy2J/dy2J of CMD is associated with NF κ B signaling up-regulation manifested by enhanced serum TNF α level, decreased I κ B- β protein level (NF κ B inhibitor) and P65 accumulation in gastrocnemius nuclei of the dy2J/dy2J mice. A more in-depth investigation revealed that Losartan induced a modification in the NF κ B gene expression towards pro-survival profile as cIAP2, TRAF2 and FTH mRNA levels were markedly increased following treatment. Losartan also induced the expression of anti-apoptotic BCl2 protein and down-regulated the expression of pro-apoptotic caspase 3 protein. Our study indicates that in the dy2J/dy2J mice of CMD, Losartan treatment resulted in NF κ B activation with shifting from apoptosis/damage targeting pathway to a profile favoring cell survival.