1. Ninjurin1 regulates striated muscle growth and differentiation
- Author
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Melanie Kny, Kitti D Csályi, Kristin Klaeske, Katharina Busch, Alexander M Meyer, Anne M Merks, Katrin Darm, Elke Dworatzek, Daniela Fliegner, Istvan Baczko, Vera Regitz-Zagrosek, Christian Butter, Friedrich C Luft, Daniela Panáková, and Jens Fielitz
- Subjects
Male ,Embryology ,Muscle Development ,Biochemistry ,Myoblasts ,Mice ,cultured myocytes ,Loss of Function Mutation ,Animal Cells ,Medicine and Health Sciences ,Morphogenesis ,Myocytes, Cardiac ,Small interfering RNAs ,Zebrafish ,Stem Cells ,Cell Differentiation ,Heart ,Animal Models ,Muscle Differentiation ,Nucleic acids ,Experimental Organism Systems ,Medicine ,Female ,Cellular Types ,Anatomy ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,Signal Transduction ,Research Article ,Science ,Cell Adhesion Molecules, Neuronal ,Muscle Tissue ,Cardiomegaly ,Mouse Models ,Research and Analysis Methods ,Model Organisms ,Genetics ,Animals ,Humans ,Nerve Growth Factors ,Non-coding RNA ,Muscle Cells ,Embryos ,Biology and Life Sciences ,Aortic Valve Stenosis ,Cell Biology ,Muscle, Striated ,Gene regulation ,Disease Models, Animal ,Biological Tissue ,Cardiovascular and Metabolic Diseases ,Cardiovascular Anatomy ,Animal Studies ,RNA ,Gene expression ,Developmental Biology - Abstract
Chronic pressure overload due to aortic valve stenosis leads to pathological cardiac hypertrophy and heart failure. Hypertrophy is accompanied by an increase in myocyte surface area, which requires a proportional increase in the number of cell-cell and cell-matrix contacts to withstand enhanced workload. In a proteomic analysis we identified nerve injury-induced protein 1 (Ninjurin1), a 16kDa transmembrane cell-surface protein involved in cell adhesion and nerve repair, to be increased in hypertrophic hearts from patients with aortic stenosis. We hypothesised that Ninjurin1 is involved in myocyte hypertrophy. We analyzed cardiac biopsies from aortic-stenosis patients and control patients undergoing elective heart surgery. We studied cardiac hypertrophy in mice after transverse aortic constriction and angiotensin II infusions, and performed mechanistic analyses in cultured myocytes. We assessed the physiological role of ninjurin1 in zebrafish during heart and skeletal muscle development. Ninjurin1 was increased in hearts of aortic stenosis patients, compared to controls, as well as in hearts from mice with cardiac hypertrophy. Besides the 16kDa Ninjurin1 (Ninjurin1-16) we detected a 24kDa variant of Ninjurin1 (Ninjurin1-24), which was predominantly expressed during myocyte hypertrophy. We disclosed that the higher molecular weight of Ninjurin1-24 was caused by N-glycosylation. Ninjurin1-16 was contained in the cytoplasm of myocytes where it colocalized with stress-fibers. In contrast, Ninjurin1-24 was localized at myocyte membranes. Gain and loss-of-function experiments showed that Ninjurin1-24 plays a role in myocyte hypertrophy and myogenic differentiation in vitro. Reduced levels of ninjurin1 impaired cardiac and skeletal muscle development in zebrafish. We conclude that Ninjurin1 contributes to myocyte growth and differentiation, and that these effects are mainly mediated by N-glycosylated Ninjurin1-24.
- Published
- 2019
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