Abstract

Muscular dystrophy is commonly caused by mutation in proteins that lead to sarcolemmal instability. However, work from several laboratories indicates that Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by defects in dysferlin expression is associated with poor healing of wounded sarcolemma. Poor healing of wounded muscles is believed to be due to poor calcium-triggered vesicle exocytosis. We have recently identified that non-dysferlin MM patient's are also poor at healing cellular wounds. Exocytosis of several different vesicles is affected by lack of dysferlin, while exocytosis of none of these vesicles appears to be deficient in non-dysferlin MM cells. Thus, it is not clear which of these (if any) vesicles are responsible for the poor healing of dysferlin deficient cells. This proposal utilizes proteomic and cell biological analysis to identify - 1) the vesicles responsible for poor healing of dysferlin-dependent and independent MM cells and 2) the molecules that regulate exocytosis of these vesicles.

Public Health Relevance

. The proposed work aims to identify cellular and molecular defect responsible for a type of muscular dystrophy associated with the inability of wounded muscle cells to heal. This work would aid in prediction, diagnosis and therapy of muscular dystrophies caused by poor healing of wounded cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055686-06
Application #
8269083
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2008-07-02
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$323,668
Indirect Cost
$135,489

  Institution

Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010

  Publications

Sreetama, Sen Chandra; Chandra, Goutam; Van der Meulen, Jack H et al. (2018) Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit. Mol Ther 26:2231-2242
Defour, Aurelia; Medikayala, Sushma; Van der Meulen, Jack H et al. (2017) Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle. Hum Mol Genet 26:1979-1991
Horn, Adam; Van der Meulen, Jack H; Defour, Aurelia et al. (2017) Mitochondrial redox signaling enables repair of injured skeletal muscle cells. Sci Signal 10:
Vila, Maria C; Rayavarapu, Sree; Hogarth, Marshall W et al. (2017) Mitochondria mediate cell membrane repair and contribute to Duchenne muscular dystrophy. Cell Death Differ 24:330-342
Sreetama, S C; Takano, T; Nedergaard, M et al. (2016) Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis. Cell Death Differ 23:596-607
Leikina, Evgenia; Defour, Aurelia; Melikov, Kamran et al. (2015) Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles. Sci Rep 5:18246
Jaiswal, Jyoti K; Lauritzen, Stine P; Scheffer, Luana et al. (2014) S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat Commun 5:3795
Scheffer, Luana L; Sreetama, Sen Chandra; Sharma, Nimisha et al. (2014) Mechanism of Ca²?-triggered ESCRT assembly and regulation of cell membrane repair. Nat Commun 5:5646
Defour, Aurelia; Sreetama, S C; Jaiswal, Jyoti K (2014) Imaging cell membrane injury and subcellular processes involved in repair. J Vis Exp :
Defour, A; Van der Meulen, J H; Bhat, R et al. (2014) Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death Dis 5:e1306

Showing the most recent 10 out of 17 publications