Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of skeletal and cardiac muscles in dysferlin-deficient SJL/J mice and wild type mice to understand the protective mechanisms against dysferlin deficiency in cardiac muscles.

ABSTRACT: Dysferlin is expressed in skeletal and cardiac muscle. However, dysferlin deficiency, namely limb girdle muscular dystrophy 2B (LGMD2B) and Myoshi myopathy, results in skeletal muscle weakness and spares the heart. This dichotomy could be caused by differential regulation of protective mechanisms. Therefore, we compared intraindividual mRNA expression profiles between cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and normal C57BL/6 mice. Experiment Overall Design: 20 chips were analyzed. They represent 4 groups of 5 replicates each. Experiment Overall Design: The 4 groups are cardiac (LV) and skeletal muscle of normal and dysferlin deficient mice. Experiment Overall Design: Tissues from normal mice are the controls in comparison to tissues of dysferlin deficient mice.

ORGANISM(S): Mus musculus

SUBMITTER: Oliver Hummel

PROVIDER: E-GEOD-2507 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy.

Wenzel Katrin K Zabojszcza Joanna J Carl Miriam M Taubert Semjon S Lass Antje A Harris Claire L CL Ho Mengfatt M Schulz Herbert H Hummel Oliver O Hubner Norbert N Osterziel Karl Josef KJ Spuler Simone S

Journal of immunology (Baltimore, Md. : 1950) 20051101 9

Dysferlin is expressed in skeletal and cardiac muscles. However, dysferlin deficiency results in skeletal muscle weakness, but spares the heart. We compared intraindividual mRNA expression profiles of cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and found down-regulation of the complement inhibitor, decay-accelerating factor/CD55, in skeletal muscle only. This finding was confirmed on mRNA and protein levels in two additional dysferlin-deficient mouse strains, A/J mice and Dysf- ...[more]

PMID: 16237120

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Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.

Dataset Information

Transcription profiling of skeletal and cardiac muscles in dysferlin-deficient SJL/J mice and wild type mice to understand the protective mechanisms against dysferlin deficiency in cardiac muscles.

Publications

Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy.

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