Many muscular dystrophies are caused by mutation in proteins that compromise the stability and integrity of the muscle sarcolemma, which results in high serum level of muscle enzymes such as Creatine Kinase. Understanding the mechanism by which healthy myofibers maintain their sarcolemmal integrity would enable development of new therapies for these muscular dystrophies. Miyoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) 2B, caused by mutations in dysferlin gene are such diseases. We have identified that loss of sarcolemmal integrity in LGMD2B muscle fibers is due to the delay in fusion of lysosome with the injured sarcolemma. This causes a delay in injury-triggered secretion of the lysosomal enzyme acid sphingomyelinase. Providing extracellular sphingomyelinase reverses the repair deficit and offers a potential therapy for LGMD2B. However, the mechanism by which alteration in sphingomyelin and other cell membrane lipids facilitates repair of injured muscle cell membranes has not been fully elucidated. This proposal aims to identify how lipids and lipid modifying enzymes such as acid sphingomyelinase facilitate maintenance of sarcolemmal integrity and facilitate repair of injured sarcolemma. We will achieve this by visualizing and modifying lipid composition of healthy muscle cell membrane and assess their effect on sarcolemmal integirty. We will also assess how lipids respond are altered in the LGMD2B patient and mouse muscle cells to identify potential therapeutic interventions to address these alterations. One such intervention we have established is the use of acid sphingomyelinase and we will evaluate its preclinical therapeutic potential for LGMD2B. These studies will not only help understand the role of lipids in maintenance of sarcolemmal integrity, but also provide insight into developing novel therapies for muscular dystrophies that move beyond targeting the proteins to also targeting the sarcolemmal lipids.
There is little understanding of the mechanism underlying the role of sarcolemmal lipids in facilitating muscle cell membrane repair. The studies proposed here is the first concerted effort to elucidate how sarcolemmal lipids respond to injury and harness this knowledge to develop novel therapies for muscular dystrophies such as LGMD2B that are associated with reduced sarcolemmal integrity.
|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|
|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|
|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:|
|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|
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