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
  • Proteins/genetics
  • Proteins/metabolism*
  • Myocardial Contraction*
  • Mice
  • Protein Interaction Mapping
  • Myocytes, Cardiac/metabolism*
  • Gene Expression Profiling/methods
  • Humans
  • Reverse Transcriptase Polymerase Chain Reaction
  • Cardiomyopathies/genetics
  • Cardiomyopathies/metabolism
  • Cardiomyopathies/physiopathology
  • Natriuretic Peptide, Brain/metabolism
  • Rats, Wistar
  • Myosin Heavy Chains/metabolism
  • Two-Hybrid System Techniques
  • Blotting, Western
  • Molecular Sequence Data
  • Amino Acid Sequence
  • Cloning, Molecular
  • Male
  • Cardiac Myosins/metabolism
  • Blotting, Northern
  • Transfection
  • Animals
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism*
  • Mice, Inbred C57BL
  • Rats, Sprague-Dawley
  • Oligonucleotide Array Sequence Analysis
  • Rats
  • Muscle, Skeletal/metabolism
  • Cells, Cultured
  • Zebrafish
  • Mechanotransduction, Cellular*
  • Protein Interaction Domains and Motifs
  • Connectin
  • Gene Expression Regulation
  • RNA Interference
  • Growth Differentiation Factor 15/metabolism
  • Stress, Mechanical
  • Sarcomeres/metabolism*
  • Serum Response Factor/metabolism
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Immunohistochemistry
  • Immunoprecipitation
  • Animals, Newborn
(all 49)
PubMed
20847312 Full text @ Circ. Res.
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
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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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.