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 language | English (US) |
|---|---|
| Pages (from-to) | 442-450 |
| Number of pages | 9 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 50 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2011 |
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Keywords
- Acidosis
- Calcium
- Contractility
- FHC
- Myofilament calcium sensitivity
- Tropomyosin
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine
Cite this
Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis. / Sheehan, Katherine A.; Arteaga, Grace M.; Hinken, Aaron C.; Dias, Fernando A.; Ribeiro, Cibele; Wieczorek, David F.; Solaro, R. John; Wolska, Beata M.
In: Journal of Molecular and Cellular Cardiology, Vol. 50, No. 3, 03.2011, p. 442-450.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis
AU - Sheehan, Katherine A.
AU - Arteaga, Grace M.
AU - Hinken, Aaron C.
AU - Dias, Fernando A.
AU - Ribeiro, Cibele
AU - Wieczorek, David F.
AU - Solaro, R. John
AU - Wolska, Beata M.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Acidosis
KW - Calcium
KW - Contractility
KW - FHC
KW - Myofilament calcium sensitivity
KW - Tropomyosin
UR - http://www.scopus.com/inward/record.url?scp=79551611313&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551611313&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2010.10.032
DO - 10.1016/j.yjmcc.2010.10.032
M3 - Article
C2 - 21047515
AN - SCOPUS:79551611313
VL - 50
SP - 442
EP - 450
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 3
ER -