Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing

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.
Circulation research   107(10): 1253-1264 (Journal)
Registered Authors
Just, Steffen, Rottbauer, Wolfgang
myocytes, cardiac, stretch, serum response factor, M-band
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Blotting, Northern
  • Blotting, Western
  • Cardiac Myosins/metabolism
  • Cardiomyopathies/genetics
  • Cardiomyopathies/metabolism
  • Cardiomyopathies/physiopathology
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Cells, Cultured
  • Cloning, Molecular
  • Connectin
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Profiling/methods
  • Gene Expression Regulation
  • Growth Differentiation Factor 15/metabolism
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Male
  • Mechanotransduction, Cellular*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism*
  • Muscle, Skeletal/metabolism
  • Myocardial Contraction*
  • Myocytes, Cardiac/metabolism*
  • Myosin Heavy Chains/metabolism
  • Natriuretic Peptide, Brain/metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Proteins/genetics
  • Proteins/metabolism*
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcomeres/metabolism*
  • Serum Response Factor/metabolism
  • Stress, Mechanical
  • Transfection
  • Two-Hybrid System Techniques
  • Zebrafish
20847312 Full text @ Circ. Res.
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
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes