UNIVERSITY OF MARYLAND

The muscular dystrophies are complex genetic diseases characterized by inherited or sporadic defects in genes that encode muscle proteins. Although Duchenne (DMD), Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss are the most common muscular dystrophies, the total number of diseases characterized as muscular dystrophies exceeds thirty (MDCARE Act, 2008). Common to all of the muscular dystrophies is progressive skeletal muscle weakness and the death of muscle cells and tissue. Although the genetic basis for most of the dystrophies is known, a disease cure may still be years away. This fact has increased the research priority mandate from researchers, family support organizations and the government (MD-CARE Act, 2008) to identify critical downstream events in the dystrophic process that can be therapeutically targeted to halt or slow the disease progression until a genetic (gene therapy) cure is realized. Transforming Growth Factor beta (TGF-Beta) signaling is pathogenic in dystrophy. Recent work by our group showed that antagonizing TGF-Beta normalizes muscle repair and restores muscle function in the well-described mdx mouse model of muscular dystrophy. To identify critical downstream transcriptional events following increased TGF-Beta signaling, we generated a tet-repressible muscle-specific TGF-Beta transgenic mouse and we find that over-expression of TGF-Beta causes muscle weakness). In related preliminary studies examining gene expression in clinical DMD muscle biopsy samples we show that the truncated form of the Brain-derived Neurotrophic Factor (BDNF) receptor, trkB.T1, but not other trkB isoforms, is highly associated with TGF-Beta expression. Further investigation revealed that genetic deletion of trkB.T1 results in a gain-of-function in neuromuscular performance, increased muscle contractility and resistance to eccentric muscle injury. Complementary gene expression studies showed that TGF-Beta and its receptor were downregulated in trkB.T1-/- muscle. An intercross between trkB.T1-/- and mdx mice to reduce trkB.T1 expression in vivo resulted in a complete rescue of dystrophy-associated loss of skeletal muscle contractility, similar to targeting TGF-Beta. We hypothesize that trkB.T1 may be a significant disease modifier of muscular dystrophy and could represent a novel therapeutic target for its treatment.

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