PUBLICATION
Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing
- Authors
- Will, R.D., Eden, M., Just, S., Hansen, A., Eder, A., Frank, D., Kuhn, C., Seeger, T.S., Oehl, U., Wiemann, S., Korn, B., Koegl, M., Rottbauer, W., Eschenhagen, T., Katus, H.A., and Frey, N.
- ID
- ZDB-PUB-101004-11
- Date
- 2010
- Source
- Circulation research 107(10): 1253-1264 (Journal)
- Registered Authors
- Just, Steffen, Rottbauer, Wolfgang
- Keywords
- myocytes, cardiac, stretch, serum response factor, M-band
- MeSH Terms
-
- Connectin
- Protein Interaction Mapping
- Mice
- Cardiac Myosins/metabolism
- Mechanotransduction, Cellular*
- Protein Interaction Domains and Motifs
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Muscle Proteins/genetics
- Muscle Proteins/metabolism*
- Mice, Inbred C57BL
- Cloning, Molecular
- Reverse Transcriptase Polymerase Chain Reaction
- Oligonucleotide Array Sequence Analysis
- Immunoprecipitation
- Amino Acid Sequence
- Gene Expression Profiling/methods
- Gene Expression Regulation
- Myocardial Contraction*
- Stress, Mechanical
- Humans
- Serum Response Factor/metabolism
- Myocytes, Cardiac/metabolism*
- Embryo, Nonmammalian/metabolism
- Transfection
- RNA Interference
- Two-Hybrid System Techniques
- Cardiomyopathies/genetics
- Cardiomyopathies/metabolism
- Cardiomyopathies/physiopathology
- Animals, Newborn
- Natriuretic Peptide, Brain/metabolism
- Animals
- Immunohistochemistry
- Blotting, Western
- Male
- Rats, Sprague-Dawley
- Blotting, Northern
- Rats
- Sarcomeres/metabolism*
- Proteins/genetics
- Proteins/metabolism*
- Muscle, Skeletal/metabolism
- Cells, Cultured
- Zebrafish
- Growth Differentiation Factor 15/metabolism
- Molecular Sequence Data
- Myosin Heavy Chains/metabolism
- Rats, Wistar
- PubMed
- 20847312 Full text @ Circ. Res.
Citation
Will, R.D., Eden, M., Just, S., Hansen, A., Eder, A., Frank, D., Kuhn, C., Seeger, T.S., Oehl, U., Wiemann, S., Korn, B., Koegl, M., Rottbauer, W., Eschenhagen, T., Katus, H.A., and Frey, N. (2010) Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing. Circulation research. 107(10):1253-1264.
Abstract
Rationale and Objective: The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band-specific proteins have been identified to date, and its exact molecular composition remains unclear. Methods and Results: Using a bioinformatic approach to identify novel heart- and muscle-specific genes, we found a leucine rich protein, myomasp (Myosin-interacting, M-band-associated stress-responsive protein)/LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor-dependent gene expression, consistent with earlier observations linking the M-band to serum response factor-mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. Conclusions: These findings reveal myomasp as a previously unrecognized component of an M-band-associated signaling pathway that regulates cardiomyocyte gene expression in response to biomechanical stress.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping