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Myomasp/LRRC39, a heart- and muscle-specific protein, is a novel component of the sarcomeric M-band and is involved in stretch sensing

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, a...

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Main Authors: Will, Rainer D. (Author) , Eden, Matthias (Author) , Just, Steffen (Author) , Hansen, Arne (Author) , Eder, Alexandra (Author) , Frank, Derk (Author) , Kuhn, Christian (Author) , Seeger, Thalia Sandra (Author) , Oehl, Ulrike (Author) , Wiemann, Stefan (Author) , Korn, Bernhard (Author) , Kögl, Manfred (Author) , Rottbauer, Wolfgang (Author) , Eschenhagen, Thomas (Author) , Katus, Hugo (Author) , Frey, Norbert (Author)
Format: Article (Journal)
Language:English
Published: November 12, 2010
In: Circulation research
Year: 2010, Volume: 107, Issue: 10, Pages: 1253-1264
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.110.222372
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCRESAHA.110.222372
Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.110.222372
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Author Notes:Rainer D. Will, Matthias Eden, Steffen Just, Arne Hansen, Alexandra Eder, Derk Frank, Christian Kuhn, Thalia S. Seeger, Ulrike Oehl, Stefan Wiemann, Bernhard Korn, Manfred Koegl, Wolfgang Rottbauer, Thomas Eschenhagen, Hugo A. Katus, and Norbert Frey
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Summary: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.
Item Description:Originally published 16 Sep 2010
Gesehen am 07.02.2024
Physical Description:Online Resource
ISSN:1524-4571
DOI:10.1161/CIRCRESAHA.110.222372

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