The muscular dystrophies are inherited disorders that largely affect striated muscle tissue resulting in progressive muscle weakness, wasting, and in many instances, premature death. Many characterized mutations in humans that cause muscular dystrophy (MD) result from alterations in structural attachment proteins that affix the underlying contractile proteins to the basal lamina, providing rigidity to the skeletal muscle cell membrane (sarcolemma). Loss of select attachment proteins in the dystrophin-glycoprotein complex (DGC) permits contraction-induced membrane tears and influx of calcium that is thought to cause cellular degeneration and necrosis of muscle fibers. During this necrotic process cytokines, chemokines and growth factors are released as part of the inflammatory and repair process, although induction of fibrosis and scarring are an unwanted side effect that worsens disease. One prominent cytokine is transforming growth factor-B ( TGFB ) that serves a master regulator ofthe fibrotic response and worsening of muscle pathology in MD. While fibroblasts are directly regulated by TGFB, other cytokines and growth factors from the myofiber are hypothesized to be necessary for fibroblast activation and a productive fibrotic response. Thus, here we will test the relatively novel hypothesis that myofibers themselves directly respond to TGFB in promoting the fibrotic response and tissue pathology in MD by generating secondary signals to resident fibroblasts. In two specific aims we will examine both the canonical (SMAD2/3) and non-canonical (TAK1-p38a-JNK) TGFB signaling pathways within myofibers to determine their role in transducing the fibrotic response outward to fibroblasts. Our approach will utilize conditional gene-targeted mice to disrupt Smad2/3 and p38a, as well as skeletal muscle-specific transgenic mice with inhibited JNK1/2 and TGFB receptor signaling. Our preliminary data show that p38a deletion in myofibers, or mice with loss of Jnk1, have reduced fibrosis and MD severity in the 6-sarcoglycan deficient background, suggesting a pathologic linkage with non-canonical TGFB signaling. Moreover, deletion of periostin, which is a TGFB -inducible extracellular matrix (ECM) protein that promotes effective TGFB signaling, similarly reduced MD severity in a mouse model of disease. These results support the overall focus of this project on TGFB signaling through the myofibers in mediating fibrosis and worsening of MD.
Accumulation of fibrotic material in the skeletal muscles of MD patients is thought to be a determinant of progressive functional decline, lack of regenerative capacity, as well as a contributor to debilitating contractures. New therapies directed at limiting the fibrotic response are desperately needed in this disease. Understanding the molecular mechanisms that lead to skeletal muscle fibrosis in MD is of the utmost importance. This Project will investigate the paracrine factors and signaling pathways that mediate tissue fibrosis in MD with the goal of identifying novel pharmacologic treatments.
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