Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis

Katherine A. Sheehan, Grace M. Arteaga, Aaron C. Hinken, Fernando A. Dias, Cibele Ribeiro, David F. Wieczorek, R. John Solaro, Beata M. Wolska

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a leading cause of sudden cardiac death among young athletes but the functional effects of the myofilament mutations during FHC-associated ischemia and acidosis, due in part to increased extravascular compressive forces and microvascular dysfunction, are not well characterized. We tested the hypothesis that the FHC-linked tropomyosin (Tm) mutation Tm-E180G alters the contractile response to acidosis via increased myofilament Ca2+ sensitivity. Intact papillary muscles from transgenic (TG) mice expressing Tm-E180G and exposed to acidic conditions (pH 6.9) exhibited a significantly smaller decrease in normalized isometric tension compared to non-transgenic (NTG) preparations. Times to peak tension and to 90% of twitch force relaxation in TG papillary muscles were significantly prolonged. Intact single ventricular TG myocytes demonstrated significantly less inhibition of unloaded shortening during moderate acidosis (pH 7.1) than NTG myocytes. The peak Ca2+ transients were not different for TG or NTG at any pH tested. The time constant of re-lengthening was slower in TG myocytes, but not the rate of Ca2+ decline. TG detergent-extracted fibers demonstrated increased Ca2+ sensitivity of force and maximal tension compared to NTG at both normal and acidic pH (pH 6.5). Tm phosphorylation was not different between TG and NTG muscles at either pH. Our data indicate that acidic pH diminished developed force in hearts of TG mice less than in NTG due to their inherently increased myofilament Ca2+ sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction.

Original languageEnglish (US)
Pages (from-to)442-450
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Acidosis
  • Calcium
  • Contractility
  • FHC
  • Myofilament calcium sensitivity
  • Tropomyosin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis'. Together they form a unique fingerprint.

  • Cite this

    Sheehan, K. A., Arteaga, G. M., Hinken, A. C., Dias, F. A., Ribeiro, C., Wieczorek, D. F., Solaro, R. J., & Wolska, B. M. (2011). Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis. Journal of Molecular and Cellular Cardiology, 50(3), 442-450. https://doi.org/10.1016/j.yjmcc.2010.10.032