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
Journal of Molecular and Cellular Cardiology 2011, 50 (3): 442-50
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 Ca(2+) 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 Ca(2+) 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 Ca(2+) decline. TG detergent-extracted fibers demonstrated increased Ca(2+) 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 Ca(2+) sensitivity, thus potentially contributing to altered energy demands and increased propensity for contractile dysfunction.

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