Loss of muscle cell adhesion is emerging as a common theme in muscular dystrophies. In skeletal muscle, the dystrophin-glycoprotein complex is located at the sarcolemma and is composed of peripheral and integral membrane proteins. As a whole, this complex links the extracellular matrix to the intracellular actin cytoskeleton and provides structural stability to the sarcolemma during muscle contraction. Duchenne muscular dystrophy, the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex. My research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have shown that sarcospan plays an important role in mediating protein interactions within this complex. Sarcospan affects communication between the dystrophin-glycoprotein complex and the extracellular matrix. Importantly, we demonstrate that mild sarcospan over-expression in mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of compensatory proteins that is functionally analogous to the dystrophin-glycoprotein complex, including a7b1 integrin. The current 4R01 proposal builds on discoveries made during the prior funding periods by interrogating specific mechanisms by which sarcospan ameliorates disease in dystrophin- deficient mdx mice. We will test the hypothesis that sarcospan enhances a7b1 integrin outside-in and inside- out signaling. We will investigate the extracellular matrix of mdx muscle that is overexpressing sarcospan to determine how sarcospan affects the composition, organization, and mechanical properties of the extracellular matrix. Lastly, we will use our decellularization protocol to isolate the extracellular matrix and test its interaction with human iPSC-derived skeletal muscle progenitors to test principles of bidirectional communication in a newly developed in vitro model system. We expect that our results will illuminate molecular pathways that counter a broad range of muscle wasting disorders due to loss of extracellular matrix contact.

Public Health Relevance

Our proposal addresses questions related to how sarcospan, a transmembrane protein expressed in skeletal and cardiac muscles, ameliorates Duchenne muscular dystrophy. We will specifically test the hypothesis that sarcospan and a7b1 integrin enhance mechanosensing functions of dystrophin-deficient muscle. We will investigate cell-extracellular matrix interactions in a newly developed in vitro assay with decellularized muscle.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Cheever, Thomas
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Gibbs, Elizabeth M; Crosbie-Watson, Rachelle H (2017) A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy. J Vis Exp :
Peter, Angela K; Miller, Gaynor; Capote, Joana et al. (2017) Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F. Skelet Muscle 7:11
McMorran, Brian J; McCarthy, Francis E; Gibbs, Elizabeth M et al. (2016) Differentiation-related glycan epitopes identify discrete domains of the muscle glycocalyx. Glycobiology 26:1120-1132
Gibbs, Elizabeth M; Marshall, Jamie L; Ma, Eva et al. (2016) High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD. Hum Mol Genet 25:5395-5406
Marshall, Jamie L; Oh, Jennifer; Chou, Eric et al. (2015) Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and ?7 integrin. Hum Mol Genet 24:2011-22
Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T et al. (2015) Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Am Heart Assoc 4:
Marshall, Jamie L; Crosbie-Watson, Rachelle H (2013) Sarcospan: a small protein with large potential for Duchenne muscular dystrophy. Skelet Muscle 3:1
Marshall, Jamie L; Kwok, Yukwah; McMorran, Brian J et al. (2013) The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy. FEBS J 280:4210-29
Marshall, Jamie L; Chou, Eric; Oh, Jennifer et al. (2012) Dystrophin and utrophin expression require sarcospan: loss of ?7 integrin exacerbates a newly discovered muscle phenotype in sarcospan-null mice. Hum Mol Genet 21:4378-93
Cabrera, Paula V; Pang, Mabel; Marshall, Jamie L et al. (2012) High throughput screening for compounds that alter muscle cell glycosylation identifies new role for N-glycans in regulating sarcolemmal protein abundance and laminin binding. J Biol Chem 287:22759-70

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