Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in α-Dystrobrevin Null Muscle

Bunnell, Tina M.; Jaeger, Michele A.; Fitzsimons, Daniel P.; Prins, Kurt W.; Ervasti, James M.

doi:10.1371/journal.pone.0002604

Cited by 20 publications

(21 citation statements)

References 44 publications

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“…Exercise tolerance was assessed by using two different methods: a rotating rod device (Rota-Rod, Ugo Basil) (13) and a treadmill Exer 3/6 model (Columbus Instruments) (35). See SI Methods.…”

Section: Methodsmentioning

confidence: 99%

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Cavalli

Justice

Boyle

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice (P = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle (P = 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue.inflammation | interleukin 37 | metabolism | AMPK | fatigue T he IL-1 family cytokine interleukin 37 (IL-37) functions as a natural suppressor of innate inflammation and acquired immunity (1). Reduction in endogenous IL-37 levels results in increased cytokine production induced by toll-like receptors (TLR) in human monocytes. In mice, IL-37 is truncated and not functional, but the human IL37 transgenic mouse exhibits reduced severity of systemic and local inflammation, as well as dampening of acquired immune responses (2-5). Moreover, administration of recombinant human IL-37 to wild-type mice also suppresses proinflammatory cytokines and curbs excessive inflammation, for example, in inflammatory arthritis (5). Recombinant IL-37 suppresses NLRP3 and IL-1β gene expression following acute lung injury (6). Recombinant IL-37 also increases insulin sensitivity in diet-induced obesity (7).The mechanism of action for IL-37 is unique in the IL-1 family. IL-37 binds to the IL-18 receptor alpha chain (IL-18Rα), but then recruits IL-1R8. IL-1R8 functions to suppress local and systemic inflammation, as well as acquired immunity (8). Indeed, recombinant IL-37 administered to mice deficient for IL-1R8 does not suppress inflammation (5, 9). The complex of IL-18Rα with IL-37 plus IL-1R8 as the coreceptor signals the cell to reduce p...

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Section: Methodsmentioning

confidence: 99%

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Cavalli

Justice

Boyle

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Published data indicated that the syntrophin-dystrobrevin complex serves as a linker between dystrophin and membranespanning complex and is important for DAPC stability (34,35). Because elevated levels of myocilin increased the association of ␣1-Syn with dystrophin (Fig.…”

Section: Overexpression Of Myocilin In Vivo Leads To Intracellularmentioning

confidence: 96%

“…5B), we hypothesized that this may increase the association of dystrophin with transmembrane proteins and contribute to the stabilization of the DAPC. To prove this hypothesis, we compared the biochemical stability of dystrophin-dystroglycan interaction using a technique described previously (35). We assessed the levels of dystrophin in the WGA glycoprotein-enriched elutes containing a high concentration of dystroglycans and their associated proteins.…”

Section: Overexpression Of Myocilin In Vivo Leads To Intracellularmentioning

confidence: 99%

Myocilin Interacts with Syntrophins and Is Member of Dystrophin-associated Protein Complex

Margetis

Kee

Tomarev

2012

Journal of Biological Chemistry

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Background:The non-ocular function(s) of myocilin, a glaucoma-associated protein, is not known. Results: Myocilin interacts with syntrophin, a component of dystrophin-associated protein complex (DAPC) and increases phosphorylation of several regulators of muscle size. Conclusion: Myocilin is involved in the muscle hypertrophy pathways acting through the components of DAPC. Significance: This is the first demonstration of myocilin functions in the skeletal muscles.

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“…31) In DAPC, α-DB could help to biochemically stabilize the interaction of dystrophin with the membrane bound dystroglycan complex in skeletal muscle cells and cardiomyocytes. 32,33) DAPC was reported to be associated with cell proliferation pathways including Notch, BMP, and Neuregulin 3 signaling pathways in muscle satellite cells. 34) Dtna N49S may affect the stability of DAPC, which causes the dysregulation of several downstream signaling pathways related to cell proliferation.…”

Section: Dtna Mutation Causes Lvnc In Micementioning

confidence: 99%

Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a <i>DTNA</i> Mutation

et al. 2017

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SummaryDTNA encoding dystrobrevin-α (α-DB) is a putative causal gene associated with left ventricular noncompaction cardiomyopathy (LVNC). The aim of the study was to investigate the causal role of DTNA in LVNC using a transgenic mouse model.A missense mutation (c.146A > G, p.N49S) of DTNA was identified in a patient with LVNC by Sanger sequencing. Six independent lines of transgenic mice expressing the mutant DTNA under a myosin heavy chain 6 (Myh6) promoter were generated (Myh6:Dtna N49S). Phenotypic characteristics of DTNA-p.N49S mutations were evaluated by echocardiography, histological observation, and immunoblotting. Multiple trabeculation and a higher ratio of non-compacted to compact myocardial layer were found in the Myh6:Dtna N49S mice compared to the controls. The transgenic mice also showed left ventricular (LV) dilation and cardiac systolic dysfunction. In conclusion, overexpression of the DTNA-p.N49S mutation in a mouse heart can be responsible for the phenotype of deep trabeculation, dilated cardiomyopathy, and cardiac dysfunction, which resembles the phenotype of LVNC.(Int Heart J 2017; 58: 939-947)

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Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in α-Dystrobrevin Null Muscle

Cited by 20 publications

References 44 publications

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Myocilin Interacts with Syntrophins and Is Member of Dystrophin-associated Protein Complex

Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a <i>DTNA</i> Mutation

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