Abstract 18079: TGF beta Signaling Drives Progression Cardiomyopathy and Muscular Dystrophy
Background: Mutations in dystrophin or its associated proteins the sarcoglycans lead to cardiomyopathy and muscular dystrophy in humans and mice. We previously generated deletions of the Drosophila melanogaster gene delta-sarcoglycan (Sgcd) that resulted in skeletal and cardiac muscle degeneration. This model develops heart tube dilation and microscopic ruptures within body muscle and also displays a progressive inability to walk against gravity in 10 second walk testing. Work from others has suggested that Transforming growth factor beta (TGFb) signaling is increased in muscular dystrophy and that blocking TGFb signaling either with neutralizing antibodies or losartan can improve aspects of muscle function. We now queried whether increased TGFb activity, in the form of SMAD signaling was pathogenic.
Methods: We investigated whether TGFb signaling is pathogenic in Sgcd deleted Drosophila using a dad-lacZ reporter to monitor TGFb activity and haploinsuffient alleles of SMAD signaling pathway.
Results: Using the dad-lacZ reporter, we found TGFb activity enhanced near the site of muscle tears. TGFb activity and signaling was reduced in flies by introducing heterozygous mutations of the co-SMAD Medea (homologous to SMAD4), or one of the two r-SMADs, MAD (SMAD1/5/8) or Smox (SMAD2/3). Mutations in Medea, Mad, or Smox restore skeletal muscle function in Sgcd mutants by completely restoring the walking dysfunction. Mutations in Medea and Smox, but not Mad, improve cardiac function as measured by optical coherence tomography.
Conclusions: Reducing SMAD activity improves cardiac and muscle function in the Sgcd model demonstrating that TGFb signaling is directly pathogenic. The differential response of cardiac and muscle function to Mad suggests that the distinct intracellular signaling pathways may be more relevant for skeletal versus cardiac muscle disease progression.
- © 2010 by American Heart Association, Inc.