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 proteins that is functionally analogous to the dystrophin-glycoprotein complex. My research group has developed the use of secondary genes, such as SSPN and Akt, as a strategy to ameliorate dystrophic muscle. Such approaches are advantages in that they have the potential to target all DMD cases, regardless of the specific dystrophin mutation. The current 3R01 proposal builds on discoveries made during the first and second funding period by interrogating specific mechanisms by which SSPN ameliorates disease in dystrophin-deficient mdx mice. We will test the efficacy of SSPN in human-derived DMD muscle cells and determine the minimal domains of SSPN that are therapeutic. Our studies will reveal a chaperone function for SSPN in determining the cell surface expression of adhesion complexes (DGC, UGC, and ?7?1 integrin) that are known to ameliorate mdx disease. We hypothesize that SSPN may function as a 'single-client'chaperone to regulate cell surface localization of adhesion complexes in muscle. The outcomes of the proposal will change our understanding of DMD pathogenesis and provide necessary insight for development of SSPN- based therapy. We will generate animal models that will be valuable for many future projects in the field. Furthermore, we expect that our results will illuminate molecular pathways that could 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 disruption of the dystrophin-glycoprotein complex causes Duchenne muscular dystrophy. During our previous funding period, we discovered that sarcospan, an integral component of the dystrophin-glycoprotein complex, is able to ameliorate dystrophin-deficient muscular dystrophy in mice. We will investigate molecular mechanisms and test the efficacy of sarcospan in patient cells.

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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Nuckolls, Glen H
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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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