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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR048179-11
Application #
8579858
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2001-09-24
Project End
2019-06-30
Budget Start
2014-07-07
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$418,335
Indirect Cost
$146,689
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Kim, Michelle H; Kay, Danielle I; Rudra, Renuka T et al. (2011) Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin-deficient mdx mice. Hum Mol Genet 20:1324-38
Peter, Angela K; Ko, Christopher Y; Kim, Michelle H et al. (2009) Myogenic Akt signaling upregulates the utrophin-glycoprotein complex and promotes sarcolemma stability in muscular dystrophy. Hum Mol Genet 18:318-27
Peter, Angela K; Marshall, Jamie L; Crosbie, Rachelle H (2008) Sarcospan reduces dystrophic pathology: stabilization of the utrophin-glycoprotein complex. J Cell Biol 183:419-27
Peter, Angela K; Miller, Gaynor; Crosbie, Rachelle H (2007) Disrupted mechanical stability of the dystrophin-glycoprotein complex causes severe muscular dystrophy in sarcospan transgenic mice. J Cell Sci 120:996-1008
Miller, Gaynor; Wang, Emily L; Nassar, Karin L et al. (2007) Structural and functional analysis of the sarcoglycan-sarcospan subcomplex. Exp Cell Res 313:639-51
Miller, Gaynor; Peter, Angela K; Espinoza, Erica et al. (2006) Over-expression of Microspan, a novel component of the sarcoplasmic reticulum, causes severe muscle pathology with triad abnormalities. J Muscle Res Cell Motil 27:545-58
Peter, Angela K; Crosbie, Rachelle H (2006) Hypertrophic response of Duchenne and limb-girdle muscular dystrophies is associated with activation of Akt pathway. Exp Cell Res 312:2580-91
Yi, Christopher E; Bekker, Janine M; Miller, Gaynor et al. (2003) Specific and potent RNA interference in terminally differentiated myotubes. J Biol Chem 278:934-9