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. We propose to investigate the molecular mechanism(s) of SSPN-mediated amelioration of mdx phenotype and reveal the compensatory mechanisms that may mask a potentially interesting and enlightening phenotype in the SSPN-null mice. We will also complete our characterization of SSPN's `rescue effect'by examining muscle mechanics. Our hypothesis provides a mechanism for cross-talk between transmembrane/cytoskeletal complexes (i.e. integrins and DGC) that may illuminate how compensatory mechanisms are regulated. Results from each of the Aims will provide new information on the role of sarcospan as an important structural element within the dystrophin-glycoprotein complex and uncover new information on sarcospan's function in signaling and disease.

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 plan to test the physiological properties of these mice and investigate the mechanisms of sarcospan amelioration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048179-10
Application #
8436292
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2001-09-24
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$301,896
Indirect Cost
$103,262
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
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