This is a renewal application to study the sarcoglycan complex in striated muscle, and specifically the role of this complex in promoting sarcolemmal stability. Mutations in the genes encoding the sarcoglycan subunits produce a fragile sarcolemma that is susceptible to disruption. Sarcolemmal disruption is a hallmark feature associated with many different etiologies of muscle and heart injury. In the case of primary sarcoglycan gene mutations, there is ongoing injury to striated muscle, both heart and skeletal muscle. In skeletal muscle, where regeneration is robust, there is insufficient regeneration to keep pace with injury, and ultimately there is replacement of myocytes and cardiomyocytes by fibrosis, leading to weakness. The process of sarcolemmal instability is seen in humans with sarcoglycan gene mutations, as it is in those with dystrophin gene mutations, since the sarcoglycans are dystrophin-associated proteins. This proposal for continued work is justified by the need to develop approaches to stabilize the sarcolemma. Such approaches, if successful, are expected to provide a potential therapeutic for individuals with sarcoglycan gene mutation. Importantly, understanding mechanisms to stabilize the sarcolemma of heart and muscle could also potential yield improved approaches towards treating or preventing other defects that compromise sarcolemmal integrity. In the prior funding period, we proposed to use an unbiased genomewide approach to map modifiers of muscular dystrophy. We successfully did this, identifying Ltbp4, the latent TGFbeta binding protein, as a modifier for murine muscular dystrophy. We extended these findings by showing that LTBP4 also modifies walking in Duchenne Muscular Dystrophy, highlighting the importance and relevance of this approach. As proposed, we used the superhealing MRL strain to identify genetic loci that modify muscle and heart function in mouse models of muscular dystrophy. We now outline experiments to study candidate modifier genes from a chromosome 9 locus that regulates the heart in muscular dystrophy. Identifying modifiers for muscular dystrophy and cardiomyopathy points to pathways that we can exploit for prognosis and ultimately for therapy since these pathways, by design, can influence the outcome of disease. Additionally, during the prior funding period, we developed significant preliminary data identifying a minimal unit of gamma-sarcoglycan that is sufficient to improve muscle and heart function. The rationale for developing and testing this minimal unit of gamma- sarcoglycan, which we termed mini-gamma, is to justify the use of exon skipping as a treatment for LGMD2C.

Public Health Relevance

This proposal outlines experiments to continue work to identify modifiers of muscular dystrophy and cardiomyopathy. Genetic modifiers are genes that alter the outcome of genetic diseases and identifying modifiers points to pathways that could be used to treat these disorders. We are also conducting experiments to determine whether exon skipping is feasible for limb girdle muscular dystrophy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Kaltman, Jonathan R
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Fallon, Justin R; McNally, Elizabeth M (2018) Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics. Matrix Biol 68-69:616-627
Ohiri, Joyce C; McNally, Elizabeth M (2018) Gene Editing and Gene-Based Therapeutics for Cardiomyopathies. Heart Fail Clin 14:179-188
Wyatt, Eugene J; Demonbreun, Alexis R; Kim, Ellis Y et al. (2018) Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. JCI Insight 3:
McNally, Elizabeth M; Wyatt, Eugene J (2017) Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. Circulation 136:979-981
McNally, Elizabeth M; Mestroni, Luisa (2017) Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. Circ Res 121:731-748
Quattrocelli, Mattia; Barefield, David Y; Warner, James L et al. (2017) Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy. J Clin Invest 127:2418-2432
Demonbreun, Alexis R; McNally, Elizabeth M (2017) Muscle cell communication in development and repair. Curr Opin Pharmacol 34:7-14
McNally, Elizabeth M (2017) Gene Editing for the Heart: Correcting Dystrophin Mutations. Circ Res 121:896-898
Quattrocelli, Mattia; Salamone, Isabella M; Page, Patrick G et al. (2017) Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy. Am J Pathol 187:2520-2535
Giacomazzi, Giorgia; Holvoet, Bryan; Trenson, Sander et al. (2017) MicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors. Nat Commun 8:1249

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