The muscular dystrophies are inherited disorders that largely affect striated muscle tissue resulting in progressive muscle weakness, wasfing, and in many instances, premature death. Many characterized mutafions in humans that cause muscular dystrophy (MD) result from alterations in structural attachment proteins that affix the underlying contracfile 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 necrofic 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-|3 (TGFp) 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 fibrofic response. Thus, here we will test the relatively novel hypothesis that myofibers themselves directly respond to TGFB in promoting the fibrofic response and fissue pathology in MD by generafing 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 fibrofic response outward to fibroblasts. Our approach will ufilize condifional 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 Jnki, have reduced fibrosis and MD severity in the 6-sarcoglycan deficient background, suggesting a pathologic linkage with non-canonical TGFp signaling. Moreover, delefion of periostin, which is a TGFp-inducible extracellular matrix (ECM) protein that promotes effective TGFp signaling, similariy 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 mediafing fibrosis and worsening of MD.

Public Health Relevance

Accumulafion of fibrofic 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 debilitafing contractures. New therapies directed at limifing the fibrofic 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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Chicago
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Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M (2017) Outside in: The matrix as a modifier of muscular dystrophy. Biochim Biophys Acta 1864:572-579
Demonbreun, Alexis R; McNally, Elizabeth M (2017) Muscle cell communication in development and repair. Curr Opin Pharmacol 34:7-14
McNally, Elizabeth M (2016) Questions and Answers About Myostatin, GDF11, and the Aging Heart. Circ Res 118:6-8
Quattrocelli, Mattia; McNally, Elizabeth M (2016) BMP and WNT: the road to cardiomyocytes is paved with precise modulation. Stem Cell Investig 3:21
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Demonbreun, Alexis R; McNally, Elizabeth M (2016) Plasma Membrane Repair in Health and Disease. Curr Top Membr 77:67-96
Lamar, Kay-Marie; Bogdanovich, Sasha; Gardner, Brandon B et al. (2016) Overexpression of Latent TGF? Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGF?. PLoS Genet 12:e1006019
Tjondrokoesoemo, Andoria; Schips, Tobias; Kanisicak, Onur et al. (2016) Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice. Hum Mol Genet 25:1192-202
Vanhoutte, Davy; Schips, Tobias G; Kwong, Jennifer Q et al. (2016) Thrombospondin expression in myofibers stabilizes muscle membranes. Elife 5:
Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison et al. (2016) Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy. J Cardiovasc Transl Res 9:85-6

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