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

• Verfasst von: Will, Rainer D. [VerfasserIn]
• Verfasst von: Eden, Matthias [VerfasserIn]
• Verfasst von: Just, Steffen [VerfasserIn]
• Verfasst von: Hansen, Arne [VerfasserIn]
• Verfasst von: Eder, Alexandra [VerfasserIn]
• Verfasst von: Frank, Derk [VerfasserIn]
• Verfasst von: Kuhn, Christian [VerfasserIn]
• Verfasst von: Seeger, Thalia Sandra [VerfasserIn]
• Verfasst von: Oehl, Ulrike [VerfasserIn]
• Verfasst von: Wiemann, Stefan [VerfasserIn]
• Verfasst von: Korn, Bernhard [VerfasserIn]
• Verfasst von: Kögl, Manfred [VerfasserIn]
• Verfasst von: Rottbauer, Wolfgang [VerfasserIn]
• Verfasst von: Eschenhagen, Thomas [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Frey, Norbert [VerfasserIn]
• Titel: Myomasp/LRRC39, a heart- and muscle-specific protein, is a novel component of the sarcomeric M-band and is involved in stretch sensing
• Verf.angabe: 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
• E-Jahr: 2010
• Jahr: November 12, 2010
• Umfang: 12 S.
• Illustrationen: Illustrationen
• Fussnoten: Originally published 16 Sep 2010 ; Gesehen am 07.02.2024
• Titel Quelle: Enthalten in: Circulation research
• Ort Quelle: New York, NY : Assoc., 1953
• Jahr Quelle: 2010
• Band/Heft Quelle: 107(2010), 10, Seite 1253-1264
• ISSN Quelle: 1524-4571
• DOI: doi:10.1161/CIRCRESAHA.110.222372
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cardiac
• Sach-SW: M-band
• Sach-SW: myocytes
• Sach-SW: serum response factor
• Sach-SW: stretch
• K10plus-PPN: 188023890X

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.